1
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Dong Q, Cheng LY. From brain-sparing to prioritised tumour growth: Insights into tumour-host interactions. Curr Opin Cell Biol 2025; 95:102560. [PMID: 40516299 DOI: 10.1016/j.ceb.2025.102560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 05/18/2025] [Accepted: 05/21/2025] [Indexed: 06/16/2025]
Abstract
Cellular responses to their environment are shaped not only by genetic composition but also by interactions with neighbouring cells. Beyond local interactions, inter-organ crosstalk has emerged as a crucial mechanism coordinating tissue growth and function. In this review, we discuss recent findings, mainly using Drosophila as a model system to investigate how organs compete for resources under metabolic stress. This mechanism ensures the prioritized growth of essential organs during development and the growth of tumours at the expense of other tissues and host fitness. Together, these studies offered valuable insights into how inter-organ communications via secreted factors and host resource reallocation are important in affecting tissue fitness and driving disease progression.
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Affiliation(s)
- Qian Dong
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, VIC 3010, Australia
| | - Louise Y Cheng
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, VIC 3010, Australia; Department of Anatomy and Physiology, The University of Melbourne, VIC 3010, Australia.
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2
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Yang D, Sun W, Gao L, Zhao K, Zhuang Q, Cai Y. Cell competition as an emerging mechanism and therapeutic target in cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167769. [PMID: 40054587 DOI: 10.1016/j.bbadis.2025.167769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/18/2025] [Accepted: 02/27/2025] [Indexed: 03/17/2025]
Abstract
Cell competition, as an internal quality control mechanism that constantly monitor cell fitness and eliminate unfit cells, maintains proper embryogenesis and tissue integrity during early development and adult homeostasis. Recent studies have revealed that cell competition functions as a tumor-suppressive mechanism to defend against cancer by removing neoplastic cell, which however, is hijacked by tumor cells and drive cell competition in favor of mutant cells, thereby promoting cancer initiation and progression. In this review, with a special focus on mammalian systems, we discuss the latest insights into the mechanisms regulating cell competition and its dual role in tumor development. We also provide current strategies to modulate the direction of cell competition for the prevention and treatment of cancers.
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Affiliation(s)
- Dakai Yang
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jintan, People's Republic of China; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, People's Republic of China.
| | - Wenyue Sun
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, People's Republic of China
| | - Lu Gao
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, People's Republic of China
| | - Kai Zhao
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jintan, People's Republic of China
| | - Qin Zhuang
- Department of General Practice, Affiliated Hospital of Jiangsu University, Zhenjiang, People's Republic of China.
| | - Yun Cai
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jintan, People's Republic of China.
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3
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Mori T, Zhou M, Kunugitani K, Akatsuka T, Yoshida Y, Kouyama-Suzuki E, Kobayashi S, Shirai Y, Tabuchi K. The Competitive Loss of Cerebellar Granule and Purkinje Cells Driven by X-Linked Mosaicism in a Female Mouse Model of CASK-Related Disorders. Cells 2025; 14:735. [PMID: 40422238 DOI: 10.3390/cells14100735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 05/10/2025] [Accepted: 05/15/2025] [Indexed: 05/28/2025] Open
Abstract
CASK-related disorders are a form of female-restricted intellectual disabilities associated with cerebellar and pontine hypoplasia. The CASK gene is regulated by X-chromosome inactivation, which results in a mosaic distribution of CASK-expressing and CASK-deficient neurons in the female brain. This mosaic distribution is believed to play a key role in the pathophysiology of X-linked neurological disorders; however, the detailed brain structure has not been extensively characterized. In this study, we used CASK heterozygous knockout (CASK-hKO) mice combined with X-linked GFP reporter mice to investigate motor abilities and the distribution of CASK-expressing cells in the brains of female CASK-hKO mice. The CASK-hKO mice exhibited motor deficits and cerebellar hypoplasia similar to those observed in patients with CASK-related disorders. Interestingly, although half of the cerebellar granule cells were CASK-negative during early postnatal development, almost all Purkinje cells and cerebellar granule cells were CASK-positive in adulthood, suggesting that CASK expression may determine the survival of cerebellar granule cells during postnatal development. We also analyzed CASK-hypomorphic mice, which express 50% less CASK than wild-type mice, and compared hemizygous males and heterozygous females. The CASK-hypomorphic heterozygous females displayed a thinner cerebellar cortex and a higher probability of CASK-positive granule cells in CASK-hKO females, suggesting that the survival of cerebellar granule cells is regulated by a combination of cell-autonomous and cell-competitive mechanisms between CASK-expressing and CASK-deficient cells, which are generated by X-chromosome inactivation. These findings provide new insights into the relationship between the mosaic distribution of cells established by X-chromosome inactivation and the pathophysiology of CASK-related disorders.
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Affiliation(s)
- Takuma Mori
- Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
- Department of Neuroinnovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto 390-8621, Japan
| | - Mengyun Zhou
- Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Ken Kunugitani
- Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Taichi Akatsuka
- Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Yukina Yoshida
- Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Emi Kouyama-Suzuki
- Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Shin Kobayashi
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan
| | - Yoshinori Shirai
- Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Katsuhiko Tabuchi
- Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
- Department of Neuroinnovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto 390-8621, Japan
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4
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Li YZ, Gao L, Sun XL, Duan L, Jiang M, Wu QF. Neural cell competition sculpting brain from cradle to grave. Natl Sci Rev 2025; 12:nwaf057. [PMID: 40309342 PMCID: PMC12042753 DOI: 10.1093/nsr/nwaf057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 01/18/2025] [Accepted: 02/13/2025] [Indexed: 05/02/2025] Open
Abstract
Darwinian selection, operating within the cellular ecosystem of multicellular organisms, drives a pervasive surveillance mechanism of cell-cell competition that shapes tissue architecture and function. While cell competition eliminates suboptimal cells to ensure tissue integrity across various tissues, neuronal competition specifically sculpts neural networks to establish precise circuits for sensory, motor and cognitive functions. However, our understanding of cell competition across diverse neural cell types in both developmental and pathological contexts remains limited. Here, we review recent advances on the phenomenon, and mechanisms and potential functions of neural cell competition (NCC), ranging from neural progenitors, neurons, astrocytes and oligodendrocytes to microglia. Physiological NCC governs cellular survival, proliferation, arborization, organization, function and territorial colonization, whereas dysregulated NCC may cause neurodevelopmental disorders, accelerate aging, exacerbate neurodegenerative diseases and drive brain tumor progression. Future work that leverages cell competition mechanisms may help to improve cognition and curb diseases.
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Affiliation(s)
- Yu Zheng Li
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Lisen Gao
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100101, China
| | - Xue-Lian Sun
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100101, China
| | - Lihui Duan
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Man Jiang
- Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qing-Feng Wu
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100101, China
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Children's Hospital, Beijing 100045, China
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5
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Komleva Y, Shpiliukova K, Bondar N, Salmina A, Khilazheva E, Illarioshkin S, Piradov M. Decoding brain aging trajectory: predictive discrepancies, genetic susceptibilities, and emerging therapeutic strategies. Front Aging Neurosci 2025; 17:1562453. [PMID: 40177249 PMCID: PMC11962000 DOI: 10.3389/fnagi.2025.1562453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 02/28/2025] [Indexed: 04/05/2025] Open
Abstract
The global extension of human lifespan has intensified the focus on aging, yet its underlying mechanisms remain inadequately understood. The article highlights aspects of genetic susceptibility to impaired brain bioenergetics, trends in age-related gene expression related to neuroinflammation and brain senescence, and the impact of stem cell exhaustion and quiescence on accelerated brain aging. We also review the accumulation of senescent cells, mitochondrial dysfunction, and metabolic disturbances as central pathological processes in aging, emphasizing how these factors contribute to inflammation and disrupt cellular competition defining the aging trajectory. Furthermore, we discuss emerging therapeutic strategies and the future potential of integrating advanced technologies to refine aging assessments. The combination of several methods including genetic analysis, neuroimaging techniques, cognitive tests and digital twins, offer a novel approach by simulating and monitoring individual health and aging trajectories, thereby providing more accurate and personalized insights. Conclusively, the accurate estimation of brain aging trajectories is crucial for understanding and managing aging processes, potentially transforming preventive and therapeutic strategies to improve health outcomes in aging populations.
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Affiliation(s)
| | | | - Nikolai Bondar
- Research Center of Neurology, Moscow, Russia
- Laboratory of Molecular Virology, First Moscow State Medical University (Sechenov University), Moscow, Russia
| | | | - Elena Khilazheva
- Department of Biological Chemistry with Courses in Medical, Research Institute of Molecular Medicine and Pathobiochemistry, Pharmaceutical and Toxicological Chemistry Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University of the Ministry of Healthcare of the Russian Federation, Krasnoyarsk, Russia
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6
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Hattori Y, Nagata K, Watanabe R, Yokoya A, Imaoka T. Super-competition as a Novel Mechanism of the Dose-rate Effect in Radiation Carcinogenesis: A Mathematical Model Study. Radiat Res 2025; 203:61-72. [PMID: 39829329 DOI: 10.1667/rade-24-00191.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 12/30/2024] [Indexed: 01/22/2025]
Abstract
Data from animal experiments show that the radiation-related risk of cancer decreases if the dose rate is reduced, even though the cumulative dose is unchanged (i.e., a dose-rate effect); however, the underlying mechanism is not well understood. To explore factors underlying the dose-rate effect observed in experimental rat mammary carcinogenesis, we developed a mathematical model that accounts for cellular dynamics during carcinogenesis, and then examined whether the model predicts cancer incidence. A mathematical model of multistage carcinogenesis involving radiation-induced cell death and mutagenesis was constructed using differential equations. The mutation rate was changed depending on the dose rate. The model also considered competition among cells with various mutation levels. The main parameters of the model were determined using previous experimental data. The parameters of the model were consistent with experimental observations. A dose-rate effect on carcinogenesis became apparent when the relationship between dose rate and mutation rate was linear quadratic or quadratic. The dose-rate effect became prominent when cells with more mutations preferentially compensated for the radiation-induced death of cells with fewer mutations. The phenomenon by which mutated cells gain a competitive advantage over normal cells is known as super-competition. Here, we identified super-competition as a novel mechanism underlying the dose-rate effects on carcinogenesis. The data also confirmed the relevance of the shape of the relationship between dose rate and the mutation rate. Thus, this study provides new evidence for the mechanism underlying the dose-rate effect, which is important for predicting the cancer-related risks of low-dose-rate irradiation.
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Affiliation(s)
- Yuya Hattori
- Faculty of Electrical Engineering and Information Science, National Institute of Technology Kure College, Hiroshima 737-8506 Japan
| | - Kento Nagata
- Department of Radiation Effects Research, Institute for Radiological Science, National Institutes for Quantum Science and Technology, Chiba-shi, Chiba 263-8555, Japan
| | - Ritsuko Watanabe
- Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba-shi 263-8555, Japan
| | - Akinari Yokoya
- Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba-shi 263-8555, Japan
| | - Tatsuhiko Imaoka
- Department of Radiation Effects Research, Institute for Radiological Science, National Institutes for Quantum Science and Technology, Chiba-shi, Chiba 263-8555, Japan
- Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba-shi 263-8555, Japan
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7
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Matsumoto K, Akieda Y, Haraoka Y, Hirono N, Sasaki H, Ishitani T. Foxo3-mediated physiological cell competition ensures robust tissue patterning throughout vertebrate development. Nat Commun 2024; 15:10662. [PMID: 39690179 PMCID: PMC11652645 DOI: 10.1038/s41467-024-55108-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 11/27/2024] [Indexed: 12/19/2024] Open
Abstract
Unfit cells with defective signalling or gene expression are eliminated through competition with neighbouring cells. However, physiological roles and mechanisms of cell competition in vertebrates remain unclear. In addition, universal mechanisms regulating diverse cell competition are unknown. Using zebrafish imaging, we reveal that cell competition ensures robust patterning of the spinal cord and muscle through elimination of cells with unfit sonic hedgehog activity, driven by cadherin-mediated communication between unfit and neighbouring fit cells and subsequent activation of the Smad-Foxo3-reactive oxygen species axis. We identify Foxo3 as a common marker of loser cells in various types of cell competition in zebrafish and mice. Foxo3-mediated physiological cell competition is required for eliminating various naturally generated unfit cells and for the consequent precise patterning during zebrafish embryogenesis and organogenesis. Given the implication of Foxo3 downregulation in age-related diseases, cell competition may be a defence system to prevent abnormalities throughout development and adult homeostasis.
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Affiliation(s)
- Kanako Matsumoto
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
- Department of Biological Sciences, Graduate School of Science, Osaka University, Suita, Osaka, Japan
| | - Yuki Akieda
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
| | - Yukinari Haraoka
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
| | - Naoki Hirono
- Laboratory for Embryogenesis, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan
| | - Hiroshi Sasaki
- Laboratory for Embryogenesis, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan
| | - Tohru Ishitani
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
- Department of Biological Sciences, Graduate School of Science, Osaka University, Suita, Osaka, Japan.
- Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka, Japan.
- Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Osaka University, Osaka, Japan.
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8
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Warren R, Klinkhammer K, Lyu H, Knopp J, Yuan T, Yao C, Stripp B, De Langhe SP. Cell competition drives bronchiolization and pulmonary fibrosis. Nat Commun 2024; 15:10624. [PMID: 39639058 PMCID: PMC11621346 DOI: 10.1038/s41467-024-54997-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive respiratory scarring disease arising from the maladaptive differentiation of lung stem cells into bronchial epithelial cells rather than into alveolar type 1 (AT1) cells, which are responsible for gas exchange. Here, we report that healthy lungs maintain their stem cells through tonic Hippo and β-catenin signaling, which promote Yap/Taz degradation and allow for low-level expression of the Wnt target gene Myc. Inactivation of upstream activators of the Hippo pathway in lung stem cells inhibits this tonic β-catenin signaling and Myc expression and promotes their Taz-mediated differentiation into AT1 cells. Vice versa, increased Myc in collaboration with Yap promotes the differentiation of lung stem cells along the basal and myoepithelial-like lineages allowing them to invade and bronchiolize the lung parenchyma in a process reminiscent of submucosal gland development. Our findings indicate that stem cells exhibiting the highest Myc levels become supercompetitors that drive remodeling, whereas loser cells with lower Myc levels terminally differentiate into AT1 cells.
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Affiliation(s)
- Rachel Warren
- Department of Medicine, Division of Pulmonary and Critical Medicine, Mayo Clinic, Rochester, MN, USA
| | - Kylie Klinkhammer
- Department of Medicine, Division of Pulmonary and Critical Medicine, Mayo Clinic, Rochester, MN, USA
| | - Handeng Lyu
- Department of Medicine, Division of Pulmonary and Critical Medicine, Mayo Clinic, Rochester, MN, USA
| | - Joseph Knopp
- Department of Medicine, Division of Pulmonary and Critical Medicine, Mayo Clinic, Rochester, MN, USA
| | - Tingting Yuan
- Department of Medicine, Division of Pulmonary, Allergy & Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Changfu Yao
- Women's Guild Lung Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Barry Stripp
- Women's Guild Lung Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Stijn P De Langhe
- Department of Medicine, Division of Pulmonary and Critical Medicine, Mayo Clinic, Rochester, MN, USA.
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9
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Raval K, Jamshidi N, Seyran B, Salwinski L, Pillai R, Yang L, Ma F, Pellegrini M, Shin J, Yang X, Tudzarova S. Dysfunctional β-cell longevity in diabetes relies on energy conservation and positive epistasis. Life Sci Alliance 2024; 7:e202402743. [PMID: 39313296 PMCID: PMC11420665 DOI: 10.26508/lsa.202402743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 09/11/2024] [Accepted: 09/12/2024] [Indexed: 09/25/2024] Open
Abstract
Long-lived PFKFB3-expressing β-cells are dysfunctional partly because of prevailing glycolysis that compromises metabolic coupling of insulin secretion. Their accumulation in type 2 diabetes (T2D) appears to be related to the loss of apoptotic competency of cell fitness competition that maintains islet function by favoring constant selection of healthy "winner" cells. To investigate how PFKFB3 can disguise the competitive traits of dysfunctional "loser" β-cells, we analyzed the overlap between human β-cells with bona fide "loser signature" across diabetes pathologies using the HPAP scRNA-seq and spatial transcriptomics of PFKFB3-positive β-cells from nPOD T2D pancreata. The overlapping transcriptional profile of "loser" β-cells was represented by down-regulated ribosomal biosynthesis and genes encoding for mitochondrial respiration. PFKFB3-positive "loser" β-cells had the reduced expression of HLA class I and II genes. Gene-gene interaction analysis revealed that PFKFB3 rs1983890 can interact with the anti-apoptotic gene MAIP1 implicating positive epistasis as a mechanism for prolonged survival of "loser" β-cells in T2D. Inhibition of PFKFB3 resulted in the clearance of dysfunctional "loser" β-cells leading to restored glucose tolerance in the mouse model of T2D.
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Affiliation(s)
- Kavit Raval
- Hillblom Islet Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Neema Jamshidi
- Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Berfin Seyran
- Hillblom Islet Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Lukasz Salwinski
- Molecular Cell and Developmental Biology, College of Life Sciences, University of California Los Angeles, Los Angeles, CA, USA
| | - Raju Pillai
- Department of Pathology, City-of-Hope, Duarte, CA, USA
| | - Lixin Yang
- Department of Pathology, City-of-Hope, Duarte, CA, USA
| | - Feiyang Ma
- Molecular Cell and Developmental Biology, College of Life Sciences, University of California Los Angeles, Los Angeles, CA, USA
| | - Matteo Pellegrini
- Molecular Cell and Developmental Biology, College of Life Sciences, University of California Los Angeles, Los Angeles, CA, USA
| | - Juliana Shin
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA
| | - Xia Yang
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA
| | - Slavica Tudzarova
- Hillblom Islet Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
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10
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Weerasinghe HN, Burrage PM, Jr DVN, Burrage K. Agent-based modeling for the tumor microenvironment (TME). MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2024; 21:7621-7647. [PMID: 39696854 DOI: 10.3934/mbe.2024335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2024]
Abstract
Cancer is a disease that arises from the uncontrolled growth of abnormal (tumor) cells in an organ and their subsequent spread into other parts of the body. If tumor cells spread to surrounding tissues or other organs, then the disease is life-threatening due to limited treatment options. This work applies an agent-based model to investigate the effect of intra-tumoral communication on tumor progression, plasticity, and invasion, with results suggesting that cell-cell and cell-extracellular matrix (ECM) interactions affect tumor cell behavior. Additionally, the model suggests that low initial healthy cell densities and ECM protein densities promote tumor progression, cell motility, and invasion. Furthermore, high ECM breakdown probabilities of tumor cells promote tumor invasion. Understanding the intra-tumoral communication under cellular stress can potentially lead to the design of successful treatment strategies for cancer.
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Affiliation(s)
- Hasitha N Weerasinghe
- School of Mathematical Sciences, Queensland University of Technology, Queensland, Brisbane, Australia
| | - Pamela M Burrage
- School of Mathematical Sciences, Queensland University of Technology, Queensland, Brisbane, Australia
| | - Dan V Nicolau Jr
- School of Immunology and Microbial Sciences, King's College London, London, United Kingdom
| | - Kevin Burrage
- School of Mathematical Sciences, Queensland University of Technology, Queensland, Brisbane, Australia
- Department of Computer Science, University of Oxford, United Kingdom
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11
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Qaisar R. The emerging roles of necroptosis in skeletal muscle health and disease. Pflugers Arch 2024; 476:1645-1651. [PMID: 39037477 DOI: 10.1007/s00424-024-02994-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/15/2024] [Accepted: 07/16/2024] [Indexed: 07/23/2024]
Abstract
Necroptosis is a regulated form of cell death with implications in various physiological and pathological processes in multiple tissues. However, the relevant findings from post-mitotic tissues, such as skeletal muscle, are scarce. This review summarizes the potential contributions of necroptosis to skeletal muscle health and diseases. It first discusses the physiological roles of necroptosis in muscle regeneration and development. It then summarizes the contributions of necroptosis to the pathogenesis of multiple muscle diseases, including muscular dystrophies, inflammatory myopathies, cachexia, and neuromuscular disorders. Lastly, it unravels the gaps in our understanding and therapeutic challenges of inhibiting necroptosis as a potential intervention for muscle diseases. Specifically, the findings from the transgenic animal models and the use of pharmacological inhibitors of necroptosis are discussed with relevance to improving the structure and/or function of skeletal muscle in various diseases. Recent developments from experimental animal models and clinical data are presented to discuss the roles of necroptosis in skeletal muscle health and diseases.
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Affiliation(s)
- Rizwan Qaisar
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates.
- Space Medicine Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates.
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates.
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12
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Vonada A, Grompe M. In vivo selection of hepatocytes. Hepatology 2024:01515467-990000000-01066. [PMID: 39787488 DOI: 10.1097/hep.0000000000001143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 09/13/2024] [Indexed: 01/12/2025]
Abstract
The liver is a highly regenerative organ capable of significant proliferation and remodeling during homeostasis and injury responses. Experiments of nature in rare genetic diseases have illustrated that healthy hepatocytes may have a selective advantage, outcompete diseased cells, and result in extensive liver replacement. This observation has given rise to the concept of therapeutic liver repopulation by providing an engineered selective advantage to a subpopulation of beneficial hepatocytes. In vivo selection can greatly enhance the efficiency of both gene and cell transplantation therapies for hepatic diseases. In vivo hepatocyte selection has also enabled the expansion of human hepatocytes in animals, creating novel models of human liver disease and biology. Finally, recent work has shown that somatic mutations produce clonal expansion of injury-resistant hepatocytes in most chronic liver diseases. In this review, we will address the role of hepatocyte selection in disease pathophysiology and therapeutic strategies.
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Affiliation(s)
- Anne Vonada
- Department of Pediatrics, Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, USA
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13
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Hodge RA, Bach EA. Mechanisms of Germline Stem Cell Competition across Species. Life (Basel) 2024; 14:1251. [PMID: 39459551 PMCID: PMC11509876 DOI: 10.3390/life14101251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/23/2024] [Accepted: 09/24/2024] [Indexed: 10/28/2024] Open
Abstract
In this review, we introduce the concept of cell competition, which occurs between heterogeneous neighboring cell populations. Cells with higher relative fitness become "winners" that outcompete cells of lower relative fitness ("losers"). We discuss the idea of super-competitors, mutant cells that expand at the expense of wild-type cells. Work on adult stem cells (ASCs) has revealed principles of neutral competition, wherein ASCs can be stochastically lost and replaced, and of biased competition, in which a winning ASC with a competitive advantage replaces its neighbors. Germline stem cells (GSCs) are ASCs that are uniquely endowed with the ability to produce gametes and, therefore, impact the next generation. Mechanisms of GSC competition have been elucidated by studies in Drosophila gonads, tunicates, and the mammalian testis. Competition between ASCs is thought to underlie various forms of cancer, including spermatocytic tumors in the human testis. Paternal age effect (PAE) disorders are caused by de novo mutations in human GSCs that increase their competitive ability and make them more likely to be inherited, leading to skeletal and craniofacial abnormalities in offspring. Given its widespread effects on human health, it is important to study GSC competition to elucidate how cells can become winners or losers.
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Affiliation(s)
| | - Erika A. Bach
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA;
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14
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Vieira R, Mariani JN, Huynh NPT, Stephensen HJT, Solly R, Tate A, Schanz S, Cotrupi N, Mousaei M, Sporring J, Benraiss A, Goldman SA. Young glial progenitor cells competitively replace aged and diseased human glia in the adult chimeric mouse brain. Nat Biotechnol 2024; 42:719-730. [PMID: 37460676 PMCID: PMC11098747 DOI: 10.1038/s41587-023-01798-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 04/20/2023] [Indexed: 08/26/2023]
Abstract
Competition among adult brain cells has not been extensively researched. To investigate whether healthy glia can outcompete diseased human glia in the adult forebrain, we engrafted wild-type (WT) human glial progenitor cells (hGPCs) produced from human embryonic stem cells into the striata of adult mice that had been neonatally chimerized with mutant Huntingtin (mHTT)-expressing hGPCs. The WT hGPCs outcompeted and ultimately eliminated their human Huntington's disease (HD) counterparts, repopulating the host striata with healthy glia. Single-cell RNA sequencing revealed that WT hGPCs acquired a YAP1/MYC/E2F-defined dominant competitor phenotype upon interaction with the host HD glia. WT hGPCs also outcompeted older resident isogenic WT cells that had been transplanted neonatally, suggesting that competitive success depended primarily on the relative ages of competing populations, rather than on the presence of mHTT. These data indicate that aged and diseased human glia may be broadly replaced in adult brain by younger healthy hGPCs, suggesting a therapeutic strategy for the replacement of aged and diseased human glia.
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Affiliation(s)
- Ricardo Vieira
- Center for Translational Neuromedicine, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark
| | - John N Mariani
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Nguyen P T Huynh
- Center for Translational Neuromedicine, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark
- Sana Biotechnology, Inc, Cambridge, MA, USA
| | - Hans J T Stephensen
- Center for Translational Neuromedicine, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark
- Department of Computer Science, University of Copenhagen Faculty of Science, Copenhagen, Denmark
| | - Renee Solly
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, USA
- Sana Biotechnology, Inc, Cambridge, MA, USA
| | - Ashley Tate
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, USA
- Sana Biotechnology, Inc, Cambridge, MA, USA
| | - Steven Schanz
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Natasha Cotrupi
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Marzieh Mousaei
- Center for Translational Neuromedicine, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark
| | - Jon Sporring
- Department of Computer Science, University of Copenhagen Faculty of Science, Copenhagen, Denmark
| | - Abdellatif Benraiss
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Steven A Goldman
- Center for Translational Neuromedicine, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark.
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, USA.
- Sana Biotechnology, Inc, Cambridge, MA, USA.
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15
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Valverde-Lopez JA, Li-Bao L, Sierra R, Santos E, Giovinazzo G, Díaz-Díaz C, Torres M. P53 and BCL-2 family proteins PUMA and NOXA define competitive fitness in pluripotent cell competition. PLoS Genet 2024; 20:e1011193. [PMID: 38489392 PMCID: PMC10971546 DOI: 10.1371/journal.pgen.1011193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 03/27/2024] [Accepted: 02/22/2024] [Indexed: 03/17/2024] Open
Abstract
Cell Competition is a process by which neighboring cells compare their fitness. As a result, viable but suboptimal cells are selectively eliminated in the presence of fitter cells. In the early mammalian embryo, epiblast pluripotent cells undergo extensive Cell Competition, which prevents suboptimal cells from contributing to the newly forming organism. While competitive ability is regulated by MYC in the epiblast, the mechanisms that contribute to competitive fitness in this context are largely unknown. Here, we report that P53 and its pro-apoptotic targets PUMA and NOXA regulate apoptosis susceptibility and competitive fitness in pluripotent cells. PUMA is widely expressed specifically in pluripotent cells in vitro and in vivo. We found that P53 regulates MYC levels in pluripotent cells, which connects these two Cell Competition pathways, however, MYC and PUMA/NOXA levels are independently regulated by P53. We propose a model that integrates a bifurcated P53 pathway regulating both MYC and PUMA/NOXA levels and determines competitive fitness.
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Affiliation(s)
- Jose A Valverde-Lopez
- Cardiovascular Regeneration Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Lin Li-Bao
- Cardiovascular Regeneration Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Rocío Sierra
- Cardiovascular Regeneration Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Elisa Santos
- Pluripotent Cell Technology Unit, Centro Nacional de Investigaciones Cardiovasculares, CNIC, Madrid, Spain
| | - Giovanna Giovinazzo
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- Pluripotent Cell Technology Unit, Centro Nacional de Investigaciones Cardiovasculares, CNIC, Madrid, Spain
| | - Covadonga Díaz-Díaz
- Cardiovascular Regeneration Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Miguel Torres
- Cardiovascular Regeneration Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
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16
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Kasper JY, Laschke MW, Koch M, Alibardi L, Magin T, Niessen CM, del Campo A. Actin-templated Structures: Nature's Way to Hierarchical Surface Patterns (Gecko's Setae as Case Study). ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2303816. [PMID: 38145336 PMCID: PMC10933612 DOI: 10.1002/advs.202303816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 11/10/2023] [Indexed: 12/26/2023]
Abstract
The hierarchical design of the toe pad surface in geckos and its reversible adhesiveness have inspired material scientists for many years. Micro- and nano-patterned surfaces with impressive adhesive performance have been developed to mimic gecko's properties. While the adhesive performance achieved in some examples has surpassed living counterparts, the durability of the fabricated surfaces is limited and the capability to self-renew and restore function-inherent to biological systems-is unimaginable. Here the morphogenesis of gecko setae using skin samples from the Bibron´s gecko (Chondrodactylus bibronii) is studied. Gecko setae develop as specialized apical differentiation structures at a distinct cell-cell layer interface within the skin epidermis. A primary role for F-actin and microtubules as templating structural elements is necessary for the development of setae's hierarchical morphology, and a stabilization role of keratins and corneus beta proteins is identified. Setae grow from single cells in a bottom layer protruding into four neighboring cells in the upper layer. The resulting multicellular junction can play a role during shedding by facilitating fracture of the cell-cell interface and release of the high aspect ratio setae. The results contribute to the understanding of setae regeneration and may inspire future concepts to bioengineer self-renewable patterned adhesive surfaces.
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Affiliation(s)
- Jennifer Y. Kasper
- INM‐Leibniz Institute for New MaterialsCampus D2 266123SaarbrueckenGermany
| | - Matthias W. Laschke
- Institute for Clinical and Experimental SurgerySaarland University66421HomburgGermany
| | - Marcus Koch
- INM‐Leibniz Institute for New MaterialsCampus D2 266123SaarbrueckenGermany
| | - Lorenzo Alibardi
- Comparative AnatomyDepartment of BiologyUniversity of Bologna& Comparative Histolab40126BolognaItaly
| | - Thomas Magin
- Division of Cell and Developmental BiologyInstitute of BiologyLeipzig University04103LeipzigGermany
| | - Carien M. Niessen
- Department Cell Biology of the SkinCologne Excellence Cluster for Stress Responses in Ageing‐associated diseases (CECAD)Center for Molecular Medicine Cologne (CMMC)University Hospital CologneUniversity of Cologne50931CologneGermany
| | - Aránzazu del Campo
- INM‐Leibniz Institute for New MaterialsCampus D2 266123SaarbrueckenGermany
- Chemistry DepartmentSaarland University66123SaarbrueckenGermany
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17
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Hof-Michel S, Cigoja L, Huhn S, Bökel C. Rel governs loser elimination during stem cell competition in the Drosophila testis. Eur J Cell Biol 2024; 103:151375. [PMID: 37995529 DOI: 10.1016/j.ejcb.2023.151375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 11/16/2023] [Accepted: 11/16/2023] [Indexed: 11/25/2023] Open
Abstract
In the Drosophila testis, a group of stromal cells termed hub provides multiple niche signals for the surrounding germline and somatic stem cells. Stem cells of both populations compete for physical retention in the niche, and clones unable to transduce any one niche signal are rapidly eliminated from the stem cell pool by differentiation. We have mapped the transcriptomes of isolated somatic cyst stem cells and differentiated cyst cells, and found that the stem cells but not their differentiated progeny exhibit the signature of an innate immune response including the NF-κB transcription factor Relish (Rel). Related signalling pathways had previously implicated in cell competition in larval epithelia, prompting the question of whether NF-κB signalling was, despite the clear differences between the two competition scenarios, also involved in stem cell competition in the testis. Here we show i) that in the testis Rel is dispensable for stemness, ii) that loss of Rel or the upstream receptor Toll suppresses loser elimination following a variety of different triggers used to induce loser fate, and iii) that clonal Rel activation is sufficient for the displacement of neutral or winner cells from the niche, even if these cells otherwise retain stem cell properties.
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Affiliation(s)
- Silvana Hof-Michel
- Dept. of Developmental Genetics, Philipps University Marburg, Karl-von-Frisch-Str. 8, 35043 Marburg, Germany
| | - Ljubinka Cigoja
- Dept. of Developmental Genetics, Philipps University Marburg, Karl-von-Frisch-Str. 8, 35043 Marburg, Germany
| | - Sabina Huhn
- Dept. of Developmental Genetics, Philipps University Marburg, Karl-von-Frisch-Str. 8, 35043 Marburg, Germany
| | - Christian Bökel
- Core Facility Confocal and Multiphoton Microscopy, Universität Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
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18
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Bird RP. Vitamin D and cancer. ADVANCES IN FOOD AND NUTRITION RESEARCH 2024; 109:92-159. [PMID: 38777419 DOI: 10.1016/bs.afnr.2023.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
The role of vitamin D in the prevention of chronic diseases including cancer, has received a great deal of attention during the past few decades. The term "Cancer" represents multiple disease states with varying biological complexities. The strongest link between vitamin D and cancer is provided by ecological and studies like observational, in preclinical models. It is apparent that vitamin D exerts diverse biological responses in a tissue specific manner. Moreover, several human factors could affect bioactivity of vitamin D. The mechanism(s) underlying vitamin D initiated anti-carcinogenic effects are diverse and includes changes at the muti-system levels. The oncogenic environment could easily corrupt the traditional role of vitamin D or could ensure resistance to vitamin D mediated responses. Several researchers have identified gaps in our knowledge pertaining to the role of vitamin D in cancer. Further areas are identified to solidify the role of vitamin D in cancer control strategies.
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Affiliation(s)
- Ranjana P Bird
- School of Health Sciences, University of Northern British Columbia, Prince George, BC, Canada.
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19
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Pak TF, Pitt-Francis J, Baker RE. A mathematical framework for the emergence of winners and losers in cell competition. J Theor Biol 2024; 577:111666. [PMID: 37956955 DOI: 10.1016/j.jtbi.2023.111666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 09/27/2023] [Accepted: 11/06/2023] [Indexed: 11/21/2023]
Abstract
Cell competition is a process in multicellular organisms where cells interact with their neighbours to determine a "winner" or "loser" status. The loser cells are eliminated through programmed cell death, leaving only the winner cells to populate the tissue. Cell competition is context-dependent; the same cell type can win or lose depending on the cell type it is competing against. Hence, winner/loser status is an emergent property. A key question in cell competition is: how do cells acquire their winner/loser status? In this paper, we propose a mathematical framework for studying the emergence of winner/loser status based on a set of quantitative criteria that distinguishes competitive from non-competitive outcomes. We apply this framework in a cell-based modelling context, to both highlight the crucial role of active cell death in cell competition and identify the factors that drive cell competition.
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Affiliation(s)
- Thomas F Pak
- Mathematical Institute, University of Oxford, Andrew Wiles Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford, OX2 6GG, UK.
| | - Joe Pitt-Francis
- Department of Computer Science, University of Oxford, Wolfson Building, Parks Road, Oxford, OX1 3QD, UK
| | - Ruth E Baker
- Mathematical Institute, University of Oxford, Andrew Wiles Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford, OX2 6GG, UK
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20
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Perez Montero S, Paul PK, di Gregorio A, Bowling S, Shepherd S, Fernandes NJ, Lima A, Pérez-Carrasco R, Rodriguez TA. Mutation of p53 increases the competitive ability of pluripotent stem cells. Development 2024; 151:dev202503. [PMID: 38131530 PMCID: PMC10820806 DOI: 10.1242/dev.202503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 12/18/2023] [Indexed: 12/23/2023]
Abstract
During development, the rate of tissue growth is determined by the relative balance of cell division and cell death. Cell competition is a fitness quality-control mechanism that contributes to this balance by eliminating viable cells that are less fit than their neighbours. The mutations that confer cells with a competitive advantage and the dynamics of the interactions between winner and loser cells are not well understood. Here, we show that embryonic cells lacking the tumour suppressor p53 are 'super-competitors' that eliminate their wild-type neighbours through the direct induction of apoptosis. This elimination is context dependent, as it does not occur when cells are pluripotent and it is triggered by the onset of differentiation. Furthermore, by combining mathematical modelling and cell-based assays we show that the elimination of wild-type cells is not through competition for space or nutrients, but instead is mediated by short-range interactions that are dependent on the local cell neighbourhood. This highlights the importance of the local cell neighbourhood and the competitive interactions within this neighbourhood for the regulation of proliferation during early embryonic development.
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Affiliation(s)
- Salvador Perez Montero
- National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
| | - Pranab K. Paul
- National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
| | - Aida di Gregorio
- National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
| | - Sarah Bowling
- National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
| | - Solomon Shepherd
- National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
| | - Nadia J. Fernandes
- Imperial BRC Genomics Facility, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
| | - Ana Lima
- National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
| | - Rubén Pérez-Carrasco
- Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
| | - Tristan A. Rodriguez
- National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
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21
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Malaguti M, Lebek T, Blin G, Lowell S. Enabling neighbour labelling: using synthetic biology to explore how cells influence their neighbours. Development 2024; 151:dev201955. [PMID: 38165174 PMCID: PMC10820747 DOI: 10.1242/dev.201955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 11/28/2023] [Indexed: 01/03/2024]
Abstract
Cell-cell interactions are central to development, but exploring how a change in any given cell relates to changes in the neighbour of that cell can be technically challenging. Here, we review recent developments in synthetic biology and image analysis that are helping overcome this problem. We highlight the opportunities presented by these advances and discuss opportunities and limitations in applying them to developmental model systems.
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Affiliation(s)
- Mattias Malaguti
- Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Tamina Lebek
- Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Guillaume Blin
- Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Sally Lowell
- Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
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22
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Tijhuis AE, Foijer F. Characterizing chromosomal instability-driven cancer evolution and cell fitness at a glance. J Cell Sci 2024; 137:jcs260199. [PMID: 38224461 DOI: 10.1242/jcs.260199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2024] Open
Abstract
Chromosomal instability (CIN), an increased rate of chromosome segregation errors during mitosis, is a hallmark of cancer cells. CIN leads to karyotype differences between cells and thus large-scale heterogeneity among individual cancer cells; therefore, it plays an important role in cancer evolution. Studying CIN and its consequences is technically challenging, but various technologies have been developed to track karyotype dynamics during tumorigenesis, trace clonal lineages and link genomic changes to cancer phenotypes at single-cell resolution. These methods provide valuable insight not only into the role of CIN in cancer progression, but also into cancer cell fitness. In this Cell Science at a Glance article and the accompanying poster, we discuss the relationship between CIN, cancer cell fitness and evolution, and highlight techniques that can be used to study the relationship between these factors. To that end, we explore methods of assessing cancer cell fitness, particularly for chromosomally unstable cancer.
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Affiliation(s)
- Andréa E Tijhuis
- European Research Institute for the Biology of Ageing , University Medical Center Groningen, University of Groningen,9713 AV Groningen, The Netherlands
| | - Floris Foijer
- European Research Institute for the Biology of Ageing , University Medical Center Groningen, University of Groningen,9713 AV Groningen, The Netherlands
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23
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Ishitani T. Cadherin-linked morphogen gradient actualizes robust tissue patterning. Curr Opin Cell Biol 2023; 85:102275. [PMID: 37944424 DOI: 10.1016/j.ceb.2023.102275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 09/30/2023] [Accepted: 10/14/2023] [Indexed: 11/12/2023]
Abstract
Morphogen gradients govern tissue patterning. These gradients provide positional information, instructing cells to adopt distinct fates. Over the past few decades, extensive studies have revealed the detailed mechanisms by which morphogens generate tissue patterns. However, the communication between morphogen-receiving cells is still poorly understood. Here, I describe how cadherin-mediated cell competition ensures robust morphogen-gradient formation. In normal zebrafish embryos, unfit cells with abnormal Wnt signaling activity spontaneously appear and produce a noisy morphogen gradient. These unfit cells communicate with neighboring cells through cadherins and are subsequently killed by cell competition. This process of killing unfit cells corrects noisy gradients to support reproducible patterning. I also discuss the significance of cell-competition-mediated morphogen-gradient correction from the perspectives of evolution and disease biology.
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Affiliation(s)
- Tohru Ishitani
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka 565-0871, Japan.
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24
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Gonzalez-Avila G, Sommer B, Flores-Soto E, Aquino-Galvez A. Hypoxic Effects on Matrix Metalloproteinases' Expression in the Tumor Microenvironment and Therapeutic Perspectives. Int J Mol Sci 2023; 24:16887. [PMID: 38069210 PMCID: PMC10707261 DOI: 10.3390/ijms242316887] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 11/14/2023] [Accepted: 11/18/2023] [Indexed: 12/18/2023] Open
Abstract
The tumor microenvironment (TME) is characterized by an acidic pH and low oxygen concentrations. Hypoxia induces neoplastic cell evasion of the immune surveillance, rapid DNA repair, metabolic reprogramming, and metastasis, mainly as a response to the hypoxic inducible factors (HIFs). Likewise, cancer cells increase matrix metalloproteinases' (MMPs) expression in response to TME conditions, allowing them to migrate from the primary tumor to different tissues. Since HIFs and MMPs are augmented in the hypoxic TME, it is easy to consider that HIFs participate directly in their expression regulation. However, not all MMPs have a hypoxia response element (HRE)-HIF binding site. Moreover, different transcription factors and signaling pathways activated in hypoxia conditions through HIFs or in a HIF-independent manner participate in MMPs' transcription. The present review focuses on MMPs' expression in normal and hypoxic conditions, considering HIFs and a HIF-independent transcription control. In addition, since the hypoxic TME causes resistance to anticancer conventional therapy, treatment approaches using MMPs as a target alone, or in combination with other therapies, are also discussed.
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Affiliation(s)
- Georgina Gonzalez-Avila
- Laboratorio de Oncología Biomédica, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas”, Calzada de Tlalpan 4502, Col. Sección XVI, Tlalpan, Ciudad de México 14080, Mexico
| | - Bettina Sommer
- Departamento de Investigación en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas”, Calzada de Tlalpan 4502, Col. Sección XVI, Tlalpan, Ciudad de México 14080, Mexico;
| | - Edgar Flores-Soto
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Coyoacán, Ciudad de México 04510, Mexico;
| | - Arnoldo Aquino-Galvez
- Laboratorio de Biología Molecular, Departamento de Fibrosis Pulmonar, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas”, Calzada de Tlalpan 4502, Col. Sección XVI, Tlalpan, Ciudad de México 14080, Mexico;
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25
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Nakai K, Lin H, Yamano S, Tanaka S, Kitamoto S, Saitoh H, Sakuma K, Kurauchi J, Akter E, Konno M, Ishibashi K, Kamata R, Ohashi A, Koseki J, Takahashi H, Yokoyama H, Shiraki Y, Enomoto A, Abe S, Hayakawa Y, Ushiku T, Mutoh M, Fujita Y, Kon S. Wnt activation disturbs cell competition and causes diffuse invasion of transformed cells through NF-κB-MMP21 pathway. Nat Commun 2023; 14:7048. [PMID: 37923722 PMCID: PMC10624923 DOI: 10.1038/s41467-023-42774-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 10/20/2023] [Indexed: 11/06/2023] Open
Abstract
Normal epithelial cells exert their competitive advantage over RasV12-transformed cells and eliminate them into the apical lumen via cell competition. However, the internal or external factors that compromise cell competition and provoke carcinogenesis remain elusive. In this study, we examine the effect of sequential accumulation of gene mutations, mimicking multi-sequential carcinogenesis on RasV12-induced cell competition in intestinal epithelial tissues. Consequently, we find that the directionality of RasV12-cell extrusion in Wnt-activated epithelia is reversed, and transformed cells are delaminated into the basal lamina via non-cell autonomous MMP21 upregulation. Subsequently, diffusively infiltrating, transformed cells develop into highly invasive carcinomas. The elevated production of MMP21 is elicited partly through NF-κB signaling, blockage of which restores apical elimination of RasV12 cells. We further demonstrate that the NF-κB-MMP21 axis is significantly bolstered in early colorectal carcinoma in humans. Collectively, this study shows that cells with high mutational burdens exploit cell competition for their benefit by behaving as unfit cells, endowing them with an invasion advantage.
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Affiliation(s)
- Kazuki Nakai
- Division of Cancer Biology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, 278-0022, Japan
| | - Hancheng Lin
- Division of Cancer Biology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, 278-0022, Japan
| | - Shotaro Yamano
- Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Kanagawa, 257-0015, Japan
| | - Shinya Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan
| | - Sho Kitamoto
- Division of Microbiology and Immunology, The WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, 565-0871, Japan
| | - Hitoshi Saitoh
- Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, 277-8577, Japan
| | - Kenta Sakuma
- Division of Cancer Biology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, 278-0022, Japan
| | - Junpei Kurauchi
- Division of Cancer Biology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, 278-0022, Japan
| | - Eilma Akter
- Division of Cancer Biology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, 278-0022, Japan
| | - Masamitsu Konno
- Division of Cancer Biology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, 278-0022, Japan
| | - Kojiro Ishibashi
- Division of Tumor Cell Biology and Bioimaging, Cancer Research Institute, Kanazawa University, Kakuma-Machi, Kanazawa, 920-1192, Japan
| | - Ryo Kamata
- Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, 277-8577, Japan
| | - Akihiro Ohashi
- Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, 277-8577, Japan
| | - Jun Koseki
- Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Hirotaka Takahashi
- Division of Cell-Free Sciences, Proteo-Science Center, Ehime University, Matsuyama, 790-8577, Japan
| | - Hideshi Yokoyama
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan
| | - Yukihiro Shiraki
- Department of Pathology, Nagoya University Hospital, Nagoya, 466-8550, Japan
| | - Atsushi Enomoto
- Department of Pathology, Nagoya University Hospital, Nagoya, 466-8550, Japan
| | - Sohei Abe
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan
| | - Michihiro Mutoh
- Department of Molecular-Targeting Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Yasuyuki Fujita
- Department of Molecular Oncology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan
| | - Shunsuke Kon
- Division of Cancer Biology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, 278-0022, Japan.
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Tarbashevich K, Ermlich L, Wegner J, Pfeiffer J, Raz E. The mitochondrial protein Sod2 is important for the migration, maintenance, and fitness of germ cells. Front Cell Dev Biol 2023; 11:1250643. [PMID: 37954204 PMCID: PMC10639133 DOI: 10.3389/fcell.2023.1250643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 10/16/2023] [Indexed: 11/14/2023] Open
Abstract
To maintain a range of cellular functions and to ensure cell survival, cells must control their levels of reactive oxygen species (ROS). The main source of these molecules is the mitochondrial respiration machinery, and the first line of defense against these toxic substances is the mitochondrial enzyme superoxide dismutase 2 (Sod2). Thus, investigating early expression patterns and functions of this protein is critical for understanding how an organism develops ways to protect itself against ROS and enhance tissue fitness. Here, we report on expression pattern and function of zebrafish Sod2, focusing on the role of the protein in migration and maintenance of primordial germ cells during early embryonic development. We provide evidence that Sod2 is involved in purifying selection of vertebrate germ cells, which can contribute to the fitness of the organism in the following generations.
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Affiliation(s)
- Katsiaryna Tarbashevich
- Institute of Cell Biology, Center for Molecular Biology of Inflammation (ZMBE), Muenster, Germany
| | - Laura Ermlich
- Institute of Cell Biology, Center for Molecular Biology of Inflammation (ZMBE), Muenster, Germany
| | - Julian Wegner
- Institute of Cell Biology, Center for Molecular Biology of Inflammation (ZMBE), Muenster, Germany
| | - Jana Pfeiffer
- Institute of Cell Biology, Center for Molecular Biology of Inflammation (ZMBE), Muenster, Germany
| | - Erez Raz
- Institute of Cell Biology, Center for Molecular Biology of Inflammation (ZMBE), Muenster, Germany
- Max Planck Institute for Molecular Biomedicine, Münster, Germany
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27
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Stuckey R, Bilbao-Sieyro C, Segura-Díaz A, Gómez-Casares MT. Molecular Studies for the Early Detection of Philadelphia-Negative Myeloproliferative Neoplasms. Int J Mol Sci 2023; 24:12700. [PMID: 37628880 PMCID: PMC10454334 DOI: 10.3390/ijms241612700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 08/07/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
JAK2 V617F is the predominant driver mutation in patients with Philadelphia-negative myeloproliferative neoplasms (MPN). JAK2 mutations are also frequent in clonal hematopoiesis of indeterminate potential (CHIP) in otherwise "healthy" individuals. However, the period between mutation acquisition and MPN diagnosis (known as latency) varies widely between individuals, with JAK2 mutations detectable several decades before diagnosis and even from birth in some individuals. Here, we will review the current evidence on the biological factors, such as additional mutations and chronic inflammation, which influence clonal expansion and may determine why some JAK2-mutated individuals will progress to an overt neoplasm during their lifetime while others will not. We will also introduce several germline variants that predispose individuals to CHIP (as well as MPN) identified from genome-wide association studies. Finally, we will explore possible mutation screening or interventions that could help to minimize MPN-associated cardiovascular complications or even delay malignant progression.
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Affiliation(s)
- Ruth Stuckey
- Hematology Department, Hospital Universitario de Gran Canaria Dr. Negrín, 35019 Las Palmas de Gran Canaria, Spain; (R.S.); (C.B.-S.); (A.S.-D.)
| | - Cristina Bilbao-Sieyro
- Hematology Department, Hospital Universitario de Gran Canaria Dr. Negrín, 35019 Las Palmas de Gran Canaria, Spain; (R.S.); (C.B.-S.); (A.S.-D.)
- Morphology Department, Universidad de Las Palmas de Gran Canaria, 35016 Las Palmas de Gran Canaria, Spain
| | - Adrián Segura-Díaz
- Hematology Department, Hospital Universitario de Gran Canaria Dr. Negrín, 35019 Las Palmas de Gran Canaria, Spain; (R.S.); (C.B.-S.); (A.S.-D.)
| | - María Teresa Gómez-Casares
- Hematology Department, Hospital Universitario de Gran Canaria Dr. Negrín, 35019 Las Palmas de Gran Canaria, Spain; (R.S.); (C.B.-S.); (A.S.-D.)
- Department of Medical Sciences, Universidad de Las Palmas de Gran Canaria, 35016 Las Palmas de Gran Canaria, Spain
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Majic P, Payne JL. Developmental Selection and the Perception of Mutation Bias. Mol Biol Evol 2023; 40:msad179. [PMID: 37556606 PMCID: PMC10443735 DOI: 10.1093/molbev/msad179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 07/22/2023] [Accepted: 07/26/2023] [Indexed: 08/11/2023] Open
Abstract
The notion that mutations are random relative to their fitness effects is central to the Neo-Darwinian view of evolution. However, a recent interpretation of the patterns of mutation accumulation in the genome of Arabidopsis thaliana has challenged this notion, arguing for the presence of a targeted DNA repair mechanism that causes a nonrandom association of mutation rates and fitness effects. Specifically, this mechanism was suggested to cause a reduction in the rates of mutations on essential genes, thus lowering the rates of deleterious mutations. Central to this argument were attempts to rule out selection at the population level. Here, we offer an alternative and parsimonious interpretation of the patterns of mutation accumulation previously attributed to mutation bias, showing how they can instead or additionally be caused by developmental selection, that is selection occurring at the cellular level during the development of a multicellular organism. Thus, the depletion of deleterious mutations in A. thaliana may indeed be the result of a selective process, rather than a bias in mutation. More broadly, our work highlights the importance of considering development in the interpretation of population-genetic analyses of multicellular organisms, and it emphasizes that efforts to identify mechanisms involved in mutational biases should explicitly account for developmental selection.
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Affiliation(s)
- Paco Majic
- Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Joshua L Payne
- Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
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29
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Deutscher K, Hillen T, Newby J. A computational model for the cancer field effect. Front Artif Intell 2023; 6:1060879. [PMID: 37469932 PMCID: PMC10352683 DOI: 10.3389/frai.2023.1060879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 06/05/2023] [Indexed: 07/21/2023] Open
Abstract
Introduction The Cancer Field Effect describes an area of pre-cancerous cells that results from continued exposure to carcinogens. Cells in the cancer field can easily develop into cancer. Removal of the main tumor mass might leave the cancer field behind, increasing risk of recurrence. Methods The model we propose for the cancer field effect is a hybrid cellular automaton (CA), which includes a multi-layer perceptron (MLP) to compute the effects of the carcinogens on the gene expression of the genes related to cancer development. We use carcinogen interactions that are typically associated with smoking and alcohol consumption and their effect on cancer fields of the tongue. Results Using simulations we support the understanding that tobacco smoking is a potent carcinogen, which can be reinforced by alcohol consumption. The effect of alcohol alone is significantly less than the effect of tobacco. We further observe that pairing tumor excision with field removal delays recurrence compared to tumor excision alone. We track cell lineages and find that, in most cases, a polyclonal field develops, where the number of distinct cell lineages decreases over time as some lineages become dominant over others. Finally, we find tumor masses rarely form via monoclonal origin.
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Capp J, Thomas F, Marusyk A, M. Dujon A, Tissot S, Gatenby R, Roche B, Ujvari B, DeGregori J, Brown JS, Nedelcu AM. The paradox of cooperation among selfish cancer cells. Evol Appl 2023; 16:1239-1256. [PMID: 37492150 PMCID: PMC10363833 DOI: 10.1111/eva.13571] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 05/19/2023] [Accepted: 06/06/2023] [Indexed: 07/27/2023] Open
Abstract
It is traditionally assumed that during cancer development, tumor cells abort their initially cooperative behavior (i.e., cheat) in favor of evolutionary strategies designed solely to enhance their own fitness (i.e., a "selfish" life style) at the expense of that of the multicellular organism. However, the growth and progress of solid tumors can also involve cooperation among these presumed selfish cells (which, by definition, should be noncooperative) and with stromal cells. The ultimate and proximate reasons behind this paradox are not fully understood. Here, in the light of current theories on the evolution of cooperation, we discuss the possible evolutionary mechanisms that could explain the apparent cooperative behaviors among selfish malignant cells. In addition to the most classical explanations for cooperation in cancer and in general (by-product mutualism, kin selection, direct reciprocity, indirect reciprocity, network reciprocity, group selection), we propose the idea that "greenbeard" effects are relevant to explaining some cooperative behaviors in cancer. Also, we discuss the possibility that malignant cooperative cells express or co-opt cooperative traits normally expressed by healthy cells. We provide examples where considerations of these processes could help understand tumorigenesis and metastasis and argue that this framework provides novel insights into cancer biology and potential strategies for cancer prevention and treatment.
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Affiliation(s)
- Jean‐Pascal Capp
- Toulouse Biotechnology InstituteUniversity of Toulouse, INSA, CNRS, INRAEToulouseFrance
| | - Frédéric Thomas
- CREEC, MIVEGECUniversity of Montpellier, CNRS, IRDMontpellierFrance
| | - Andriy Marusyk
- Department of Cancer PhysiologyH Lee Moffitt Cancer Center and Research InstituteTampaFloridaUSA
| | - Antoine M. Dujon
- Centre for Integrative Ecology, School of Life and Environmental SciencesDeakin UniversityGeelongVictoriaAustralia
| | - Sophie Tissot
- Department of Biochemistry and Molecular GeneticsUniversity of Colorado Anschutz Medical CampusAuroraColoradoUSA
| | - Robert Gatenby
- Department of Cancer PhysiologyH Lee Moffitt Cancer Center and Research InstituteTampaFloridaUSA
| | - Benjamin Roche
- Department of Biochemistry and Molecular GeneticsUniversity of Colorado Anschutz Medical CampusAuroraColoradoUSA
| | - Beata Ujvari
- Centre for Integrative Ecology, School of Life and Environmental SciencesDeakin UniversityGeelongVictoriaAustralia
| | - James DeGregori
- Department of Biochemistry and Molecular GeneticsUniversity of Colorado Anschutz Medical CampusAuroraColoradoUSA
| | - Joel S. Brown
- Department of Cancer PhysiologyH Lee Moffitt Cancer Center and Research InstituteTampaFloridaUSA
| | - Aurora M. Nedelcu
- Department of BiologyUniversity of New BrunswickFrederictonNew BrunswickCanada
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Tshering LF, Luo F, Russ S, Szenk M, Rubel D, Tutuska K, Rail JG, Balázsi G, Shen MM, Talos F. Immune mechanisms shape the clonal landscape during early progression of prostate cancer. Dev Cell 2023; 58:1071-1086.e8. [PMID: 37148881 PMCID: PMC10330387 DOI: 10.1016/j.devcel.2023.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 12/18/2022] [Accepted: 04/14/2023] [Indexed: 05/08/2023]
Abstract
Understanding the role of the immune microenvironment in modulating intratumor heterogeneity is essential for effective cancer therapies. Using multicolor lineage tracing in genetically engineered mouse models and single-cell transcriptomics, we show that slowly progressing tumors contain a multiclonal landscape of relatively homogeneous subpopulations within a well-organized tumor microenvironment. In more advanced and aggressive tumors, however, the multiclonal landscape develops into competing dominant and minor clones accompanied by a disordered microenvironment. We demonstrate that this dominant/minor landscape is associated with differential immunoediting, in which minor clones are marked by an increased expression of IFNγ-response genes and the T cell-activating chemokines Cxcl9 and Cxcl11. Furthermore, immunomodulation of the IFNγ pathway can rescue minor clones from elimination. Notably, the immune-specific gene signature of minor clones exhibits a prognostic value for biochemical recurrence-free survival in human prostate cancer. These findings suggest new immunotherapy approaches for modulating clonal fitness and tumor progression in prostate cancer.
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Affiliation(s)
- Lara F Tshering
- Department of Urology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Fu Luo
- Department of Urology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Savanah Russ
- Department of Urology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Mariola Szenk
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794, USA; Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Diana Rubel
- Department of Urology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Karis Tutuska
- Department of Urology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA
| | - James G Rail
- Department of Urology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Gábor Balázsi
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794, USA; Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Michael M Shen
- Departments of Medicine, Genetics & Development, Urology, and Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
| | - Flaminia Talos
- Department of Urology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA; Departments of Medicine, Genetics & Development, Urology, and Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA.
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Yu T, Kuang H, Wu X, Huang Y, Wang J, Wen Z. Cell competition for neuron-derived trophic factor controls the turnover and lifespan of microglia. SCIENCE ADVANCES 2023; 9:eadf9790. [PMID: 37327343 PMCID: PMC10275588 DOI: 10.1126/sciadv.adf9790] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 05/10/2023] [Indexed: 06/18/2023]
Abstract
Microglia are brain-resident macrophages capable of long-term maintenance through self-renewal. Yet the mechanism governing the turnover and lifespan of microglia remains unknown. In zebrafish, microglia arise from two sources, rostral blood island (RBI) and aorta-gonad-mesonephros (AGM). The RBI-derived microglia are born early but have a short lifespan and diminish in adulthood, while the AGM-derived microglia emerge later and are capable of long-term maintenance in adulthood. Here, we show that the attenuation of RBI microglia is due to their less competitiveness for neuron-derived interleukin-34 (Il34) caused by age-dependent decline of colony-stimulating factor-1 receptor a (csf1ra). Alterations of Il34/Csf1ra levels and removal of AGM microglia revamp the proportion and lifespan of RBI microglia. The csf1ra/CSF1R expression in zebrafish AGM-derived microglia and murine adult microglia also undergo age-dependent decline, leading to the elimination of aged microglia. Our study reveals cell competition as a general mechanism controlling the turnover and lifespan of microglia.
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Affiliation(s)
- Tao Yu
- Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University-the Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China
- Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen 518055, China
| | - Haoyue Kuang
- Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University-the Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China
| | - Xiaohai Wu
- Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen 518055, China
| | - Ying Huang
- Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen 518055, China
| | - Jianzhong Wang
- Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen 518055, China
| | - Zilong Wen
- Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University-the Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China
- Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen 518055, China
- Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China
- Department of Immunology and Microbiology, School of Life Science, Southern University of Science and Technology, Shenzhen 518055, China
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Huang Y, Gui J, Myllymäki SM, Mikkola ML, Shimmi O. Coordination of tissue homeostasis and growth by the Scribble-α-Catenin-Septate junction complex. iScience 2023; 26:106490. [PMID: 37096043 PMCID: PMC10122046 DOI: 10.1016/j.isci.2023.106490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/27/2023] [Accepted: 03/18/2023] [Indexed: 04/26/2023] Open
Abstract
Maintaining apicobasal polarity (ABP) is crucial for epithelial integrity and homeostasis during tissue development. Although intracellular mechanisms underlying ABP establishment have been well studied, it remains to be addressed how the ABP coordinates tissue growth and homeostasis. By studying Scribble, a key ABP determinant, we address molecular mechanisms underlying ABP-mediated growth control in the Drosophila wing imaginal disc. Our data reveal that genetic and physical interactions between Scribble, Septate junction complex and α-Catenin appear to be key for sustaining ABP-mediated growth control. Cells with conditional scribble knockdown instigate the loss of α-Catenin, ultimately leading to the formation of neoplasia accompanying with activation of Yorkie. In contrast, cells expressing wild type scribble progressively restore ABP in scribble hypomorphic mutant cells in a non-autonomous manner. Our findings provide unique insights into cellular communication among optimal and sub-optimal cells to regulate epithelial homeostasis and growth.
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Affiliation(s)
- Yunxian Huang
- Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland
| | - Jinghua Gui
- Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland
| | | | - Marja L. Mikkola
- Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland
| | - Osamu Shimmi
- Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland
- Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia
- Corresponding author
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Otsuka K, Iwasaki T. Insights into radiation carcinogenesis based on dose-rate effects in tissue stem cells. Int J Radiat Biol 2023; 99:1503-1521. [PMID: 36971595 DOI: 10.1080/09553002.2023.2194398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 03/16/2023] [Indexed: 03/29/2023]
Abstract
PURPOSE Increasing epidemiological and biological evidence suggests that radiation exposure enhances cancer risk in a dose-dependent manner. This can be attributed to the 'dose-rate effect,' where the biological effect of low dose-rate radiation is lower than that of the same dose at a high dose-rate. This effect has been reported in epidemiological studies and experimental biology, although the underlying biological mechanisms are not completely understood. In this review, we aim to propose a suitable model for radiation carcinogenesis based on the dose-rate effect in tissue stem cells. METHODS We surveyed and summarized the latest studies on the mechanisms of carcinogenesis. Next, we summarized the radiosensitivity of intestinal stem cells and the role of dose-rate in the modulation of stem-cell dynamics after irradiation. RESULTS Consistently, driver mutations can be detected in most cancers from past to present, supporting the hypothesis that cancer progression is initiated by the accumulation of driver mutations. Recent reports demonstrated that driver mutations can be observed even in normal tissues, which suggests that the accumulation of mutations is a necessary condition for cancer progression. In addition, driver mutations in tissue stem cells can cause tumors, whereas they are not sufficient when they occur in non-stem cells. For non-stem cells, tissue remodeling induced by marked inflammation after the loss of tissue cells is important in addition to the accumulation of mutations. Therefore, the mechanism of carcinogenesis differs according to the cell type and magnitude of stress. In addition, our results indicated that non-irradiated stem cells tend to be eliminated from three-dimensional cultures of intestinal stem cells (organoids) composed of irradiated and non-irradiated stem cells, supporting the stem-cell competition. CONCLUSIONS We propose a unique scheme in which the dose-rate dependent response of intestinal stem cells incorporates the concept of the threshold of stem-cell competition and context-dependent target shift from stem cells to whole tissue. The concept highlights four key issues that should be considered in radiation carcinogenesis: i.e. accumulation of mutations; tissue reconstitution; stem-cell competition; and environmental factors like epigenetic modifications.
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Affiliation(s)
- Kensuke Otsuka
- Biology and Environmental Chemistry Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry, Tokyo, Japan
| | - Toshiyasu Iwasaki
- Strategy and Planning Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry, Tokyo, Japan
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Gromova T, Gehred ND, Vondriska TM. Single-cell transcriptomes in the heart: when every epigenome counts. Cardiovasc Res 2023; 119:64-78. [PMID: 35325060 PMCID: PMC10233279 DOI: 10.1093/cvr/cvac040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 02/03/2022] [Accepted: 02/14/2022] [Indexed: 11/13/2022] Open
Abstract
The response of an organ to stimuli emerges from the actions of individual cells. Recent cardiac single-cell RNA-sequencing studies of development, injury, and reprogramming have uncovered heterogeneous populations even among previously well-defined cell types, raising questions about what level of experimental resolution corresponds to disease-relevant, tissue-level phenotypes. In this review, we explore the biological meaning behind this cellular heterogeneity by undertaking an exhaustive analysis of single-cell transcriptomics in the heart (including a comprehensive, annotated compendium of studies published to date) and evaluating new models for the cardiac function that have emerged from these studies (including discussion and schematics that depict new hypotheses in the field). We evaluate the evidence to support the biological actions of newly identified cell populations and debate questions related to the role of cell-to-cell variability in development and disease. Finally, we present emerging epigenomic approaches that, when combined with single-cell RNA-sequencing, can resolve basic mechanisms of gene regulation and variability in cell phenotype.
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Affiliation(s)
- Tatiana Gromova
- Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Department of Medicine/Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Natalie D Gehred
- Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Department of Medicine/Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Thomas M Vondriska
- Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Department of Medicine/Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
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Swiatczak B. Evolution within the body: the rise and fall of somatic Darwinism in the late nineteenth century. HISTORY AND PHILOSOPHY OF THE LIFE SCIENCES 2023; 45:8. [PMID: 36862350 DOI: 10.1007/s40656-023-00566-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 11/25/2022] [Indexed: 06/18/2023]
Abstract
Originating in the work of Ernst Haeckel and Wilhelm Preyer, and advanced by a Prussian embryologist, Wilhelm Roux, the idea of struggle for existence between body parts helped to establish a framework, in which population cell dynamics rather than a predefined harmony guides adaptive changes in an organism. Intended to provide a causal-mechanical view of functional adjustments in body parts, this framework was also embraced later by early pioneers of immunology to address the question of vaccine effectiveness and pathogen resistance. As an extension of these early efforts, Elie Metchnikoff established an evolutionary vision of immunity, development, pathology, and senescence, in which phagocyte-driven selection and struggle promote adaptive changes in an organism. Despite its promising start, the idea of somatic evolution lost its appeal at the turn of the twentieth century giving way to a vision, in which an organism operates as a genetically uniform, harmonious entity.
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Affiliation(s)
- Bartlomiej Swiatczak
- Department of History of Science and Scientific Archaeology, University of Science and Technology of China, 96 Jinzhai Rd. 230026, Hefei, P. R. China.
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Ueno M, Yoshii K, Yamashita T, Sonomura K, Asada K, Ito E, Fujita T, Sotozono C, Kinoshita S, Hamuro J. The Interplay between Metabolites and MicroRNAs in Aqueous Humor to Coordinate Corneal Endothelium Integrity. OPHTHALMOLOGY SCIENCE 2023; 3:100299. [PMID: 37125267 PMCID: PMC10141542 DOI: 10.1016/j.xops.2023.100299] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 03/07/2023] [Accepted: 03/08/2023] [Indexed: 03/17/2023]
Abstract
Purpose The purpose of the study was to clarify the interplay between metabolites and microRNAs (miRs) in the aqueous humor (AqH) of bullous keratopathy (BK) patients to retain human corneal endothelium (HCE) integrity. Design Prospective, comparative, observational study. Participants A total of 55 patients with BK and 31 patients with cataract (Cat) as control. Methods A biostatic analysis of miRs and metabolites in the AqH, hierarchical clustering, and a least absolute shrinkage and selection operator (Lasso) analysis were employed. The miR levels in AqH of BK (n = 18) and Cat (n = 8) patients were determined using 3D-Gene human miR chips. Hierarchical clusters of metabolites detected by liquid chromatography-mass spectrometry or gas chromatography-mass spectrometry in AqH specimens from 2 disease groups, BK (total n = 55) and Cat (total n = 31), were analyzed twice to confirm the reproducibility. The analytical procedure applied for investigating the association between metabolites and miRs in AqH was the exploratory data analysis of biostatistics to avoid any kind of prejudice. This research procedure includes a heat-map, cluster analysis, feature extraction techniques by principal component analysis, and a regression analysis method by Lasso. The cellular and released miR levels were validated using reverse transcription polymerase chain reaction and mitochondria membrane potential was assessed to determine the functional features of the released miRs. Main Outcome Measures Identification of interacting metabolites and miRs in AqH attenuating HCE degeneration. Results The metabolites that decreased in the AqH of BK patients revealed that 3-hydroxyisobutyric acid (HIB), 2-aminobutyric acid (AB) and branched-chain amino acids, and serine were categorized into the same cluster by hierarchical clustering of metabolites. The positive association of HIB with miR-34a-5p was confirmed (P = 0.018), and the Lasso analysis identified the interplay between miR-34a-5p and HIB, between miR-24-3p and AB, and between miR-34c-5p and serine (P = 0.041, 0.027, and 0.009, respectively). 3-hydroxyisobutyric acid upregulated the cellular miR-34a expression, mitochondrial membrane potential, and release of miR-184 in dedifferentiated cultured HCE cells. Conclusions Metabolites and miRs in AqH may synchronize in ensuring the integrity of the HCE to maintain efficient dehydration from the stroma. Financial Disclosures Proprietary or commercial disclosure may be found after the references.
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Affiliation(s)
- Morio Ueno
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kengo Yoshii
- Department of Mathematics and Statistics in Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomoko Yamashita
- Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazuhiro Sonomura
- Life Science Research Center, Technology Research Laboratory, Shimadzu Corporation, Kyoto, Japan
| | - Kazuko Asada
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Eiko Ito
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomoko Fujita
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Chie Sotozono
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shigeru Kinoshita
- Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Junji Hamuro
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Correspondence: Junji Hamuro, PhD, Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto 602-0841, Japan.
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Shafritz DA, Ebrahimkhani MR, Oertel M. Therapeutic Cell Repopulation of the Liver: From Fetal Rat Cells to Synthetic Human Tissues. Cells 2023; 12:529. [PMID: 36831196 PMCID: PMC9954009 DOI: 10.3390/cells12040529] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/20/2023] [Accepted: 01/26/2023] [Indexed: 02/10/2023] Open
Abstract
Progenitor cells isolated from the fetal liver can provide a unique cell source to generate new healthy tissue mass. Almost 20 years ago, it was demonstrated that rat fetal liver cells repopulate the normal host liver environment via a mechanism akin to cell competition. Activin A, which is produced by hepatocytes, was identified as an important player during cell competition. Because of reduced activin receptor expression, highly proliferative fetal liver stem/progenitor cells are resistant to activin A and therefore exhibit a growth advantage compared to hepatocytes. As a result, transplanted fetal liver cells are capable of repopulating normal livers. Important for cell-based therapies, hepatic stem/progenitor cells containing repopulation potential can be separated from fetal hematopoietic cells using the cell surface marker δ-like 1 (Dlk-1). In livers with advanced fibrosis, fetal epithelial stem/progenitor cells differentiate into functional hepatic cells and out-compete injured endogenous hepatocytes, which cause anti-fibrotic effects. Although fetal liver cells efficiently repopulate the liver, they will likely not be used for human cell transplantation. Thus, utilizing the underlying mechanism of repopulation and developed methods to produce similar growth-advantaged cells in vitro, e.g., human induced pluripotent stem cells (iPSCs), this approach has great potential for developing novel cell-based therapies in patients with liver disease. The present review gives a brief overview of the classic cell transplantation models and various cell sources studied as donor cell candidates. The advantages of fetal liver-derived stem/progenitor cells are discussed, as well as the mechanism of liver repopulation. Moreover, this article reviews the potential of in vitro developed synthetic human fetal livers from iPSCs and their therapeutic benefits.
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Affiliation(s)
- David A. Shafritz
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Mo R. Ebrahimkhani
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15213, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Michael Oertel
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15213, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
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Sarmah H, Sawada A, Hwang Y, Miura A, Shimamura Y, Tanaka J, Yamada K, Mori M. Towards human organ generation using interspecies blastocyst complementation: Challenges and perspectives for therapy. Front Cell Dev Biol 2023; 11:1070560. [PMID: 36743411 PMCID: PMC9893295 DOI: 10.3389/fcell.2023.1070560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 01/05/2023] [Indexed: 01/20/2023] Open
Abstract
Millions of people suffer from end-stage refractory diseases. The ideal treatment option for terminally ill patients is organ transplantation. However, donor organs are in absolute shortage, and sadly, most patients die while waiting for a donor organ. To date, no technology has achieved long-term sustainable patient-derived organ generation. In this regard, emerging technologies of chimeric human organ production via blastocyst complementation (BC) holds great promise. To take human organ generation via BC and transplantation to the next step, we reviewed current emerging organ generation technologies and the associated efficiency of chimera formation in human cells from the standpoint of developmental biology.
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Affiliation(s)
- Hemanta Sarmah
- Department of Medicine, Columbia Center for Human Development, Columbia University Medical Center, New York, NY, United States
| | - Anri Sawada
- Department of Medicine, Columbia Center for Human Development, Columbia University Medical Center, New York, NY, United States
| | - Youngmin Hwang
- Department of Medicine, Columbia Center for Human Development, Columbia University Medical Center, New York, NY, United States
| | - Akihiro Miura
- Department of Medicine, Columbia Center for Human Development, Columbia University Medical Center, New York, NY, United States
| | - Yuko Shimamura
- Department of Medicine, Columbia Center for Human Development, Columbia University Medical Center, New York, NY, United States
| | - Junichi Tanaka
- Department of Medicine, Columbia Center for Human Development, Columbia University Medical Center, New York, NY, United States
| | - Kazuhiko Yamada
- Department of Surgery, Johns Hopkins University, Baltimore, MD, United States
| | - Munemasa Mori
- Department of Medicine, Columbia Center for Human Development, Columbia University Medical Center, New York, NY, United States
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40
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Li K, Huo Q, Li BY, Yokota H. The Double-Edged Proteins in Cancer Proteomes and the Generation of Induced Tumor-Suppressing Cells (iTSCs). Proteomes 2023; 11:5. [PMID: 36810561 PMCID: PMC9944087 DOI: 10.3390/proteomes11010005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/15/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Unlike a prevalent expectation that tumor cells secrete tumor-promoting proteins and stimulate the progression of neighboring tumor cells, accumulating evidence indicates that the role of tumor-secreted proteins is double-edged and context-dependent. Some of the oncogenic proteins in the cytoplasm and cell membranes, which are considered to promote the proliferation and migration of tumor cells, may inversely act as tumor-suppressing proteins in the extracellular domain. Furthermore, the action of tumor-secreted proteins by aggressive "super-fit" tumor cells can be different from those derived from "less-fit" tumor cells. Tumor cells that are exposed to chemotherapeutic agents could alter their secretory proteomes. Super-fit tumor cells tend to secrete tumor-suppressing proteins, while less-fit or chemotherapeutic agent-treated tumor cells may secrete tumor-promotive proteomes. Interestingly, proteomes derived from nontumor cells such as mesenchymal stem cells and peripheral blood mononuclear cells mostly share common features with tumor cell-derived proteomes in response to certain signals. This review introduces the double-sided functions of tumor-secreted proteins and describes the proposed underlying mechanism, which would possibly be based on cell competition.
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Affiliation(s)
- Kexin Li
- Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
| | - Qingji Huo
- Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
| | - Bai-Yan Li
- Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Hiroki Yokota
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA
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Kim K, Huang H, Parida PK, He L, Marquez-Palencia M, Reese TC, Kapur P, Brugarolas J, Brekken RA, Malladi S. Cell Competition Shapes Metastatic Latency and Relapse. Cancer Discov 2023; 13:85-97. [PMID: 36098678 PMCID: PMC9839468 DOI: 10.1158/2159-8290.cd-22-0236] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 07/21/2022] [Accepted: 09/06/2022] [Indexed: 01/17/2023]
Abstract
Cell competition, a fitness-sensing process, is essential for tissue homeostasis. Using cancer metastatic latency models, we show that cell competition results in the displacement of latent metastatic (Lat-M) cells from the primary tumor. Lat-M cells resist anoikis and survive as residual metastatic disease. A memodeled extracellular matrix facilitates Lat-M cell displacement and survival in circulation. Disrupting cell competition dynamics by depleting secreted protein and rich in cysteine (SPARC) reduced displacement from orthotopic tumors and attenuated metastases. In contrast, depletion of SPARC after extravasation in lung-resident Lat-M cells increased metastatic outgrowth. Furthermore, multiregional transcriptomic analyses of matched primary tumors and metachronous metastases from patients with kidney cancer identified tumor subclones with Lat-M traits. Kidney cancer enriched for these Lat-M traits had a rapid onset of metachronous metastases and significantly reduced disease-free survival. Thus, an unexpected consequence of cell competition is the displacement of cells with Lat-M potential, thereby shaping metastatic latency and relapse. SIGNIFICANCE We demonstrate that cell competition within the primary tumor results in the displacement of Lat-M cells. We further show the impact of altering cell competition dynamics on metastatic incidence that may guide strategies to limit metastatic recurrences. This article is highlighted in the In This Issue feature, p. 1.
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Affiliation(s)
- Kangsan Kim
- Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.,Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
| | - Huocong Huang
- Hamon Center for Therapeutic Oncology Research and Department of Surgery, UT Southwestern Medical Center, Dallas, Texas
| | - Pravat Kumar Parida
- Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.,Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
| | - Lan He
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Mauricio Marquez-Palencia
- Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.,Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
| | - Tanner C Reese
- Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Department of Urology, UT Southwestern Medical Center, Dallas, Texas
| | - Payal Kapur
- Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.,Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, UT Southwestern Medical Center, Dallas, Texas
| | - James Brugarolas
- Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, UT Southwestern Medical Center, Dallas, Texas.,Hematology-Oncology Division, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Rolf A Brekken
- Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Hamon Center for Therapeutic Oncology Research and Department of Surgery, UT Southwestern Medical Center, Dallas, Texas
| | - Srinivas Malladi
- Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.,Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
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42
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Evo-devo perspectives on cancer. Essays Biochem 2022; 66:797-815. [PMID: 36250956 DOI: 10.1042/ebc20220041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 09/22/2022] [Accepted: 09/26/2022] [Indexed: 12/13/2022]
Abstract
The integration of evolutionary and developmental approaches into the field of evolutionary developmental biology has opened new areas of inquiry- from understanding the evolution of development and its underlying genetic and molecular mechanisms to addressing the role of development in evolution. For the last several decades, the terms 'evolution' and 'development' have been increasingly linked to cancer, in many different frameworks and contexts. This mini-review, as part of a special issue on Evolutionary Developmental Biology, discusses the main areas in cancer research that have been addressed through the lenses of both evolutionary and developmental biology, though not always fully or explicitly integrated in an evo-devo framework. First, it briefly introduces the current views on carcinogenesis that invoke evolutionary and/or developmental perspectives. Then, it discusses the main mechanisms proposed to have specifically evolved to suppress cancer during the evolution of multicellularity. Lastly, it considers whether the evolution of multicellularity and development was shaped by the threat of cancer (a cancer-evo-devo perspective), and/or whether the evolution of developmental programs and life history traits can shape cancer resistance/risk in various lineages (an evo-devo-cancer perspective). A proper evolutionary developmental framework for cancer, both as a disease and in terms of its natural history (in the context of the evolution of multicellularity and development as well as life history traits), could bridge the currently disparate evolutionary and developmental perspectives and uncover aspects that will provide new insights for cancer prevention and treatment.
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Yamashita T, Asada K, Ueno M, Hiramoto N, Fujita T, Toda M, Sotozono C, Kinoshita S, Hamuro J. Cellular Interplay Through Extracellular Vesicle miR-184 Alleviates Corneal Endothelium Degeneration. OPHTHALMOLOGY SCIENCE 2022; 2:100212. [PMID: 36531590 PMCID: PMC9755023 DOI: 10.1016/j.xops.2022.100212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 08/03/2022] [Accepted: 08/04/2022] [Indexed: 05/25/2023]
Abstract
OBJECTIVE The objective of the study was to reveal the presence of cellular interplay through extracellular vesicle (EV) microRNAs (miRs), to dampen the vicious cycle to degenerate human corneal endothelium (HCE) tissues. DESIGN Prospective, comparative, observational study. METHODS The miR levels in neonate-derived corneal tissues, in the aqueous humor (AqH) of bullous keratoplasty and cataract patients, as well as in the culture supernatant (CS) and EV of cultured human corneal endothelial cells (hCECs), were determined using 3D-Gene human miR chips and then validated using the real-time polymerase chain reaction. The extracellularly released miRs were profiled after the forced downregulation of cellular miR-34a, either by an miR-34a inhibitor or exposure to H2O2. The senescence-associated secretory phenotypes and mitochondrial membrane potential (MMP) were assessed to determine the functional features of the released miRs. MAIN OUTCOME MEASURES Identification of functional miRs attenuating HCE degeneration. RESULTS The miRs in AqH were classified into 2 groups: expression in 1 group was significantly reduced in neonate-derived tissues, whereas that in the other group remained almost constant, independent of aging. The miR-34a and -29 families were typical in the former group, whereas miR-184 and -24-3p were typical in the latter. Additionally, a larger amount of the latter miRs was detected in AqH compared with those of the former miRs. There was also a greater abundance of miR-184 and -24-3p in hCECs, EV, and CS in fully mature CD44-/dull hCEC, leading to sufficient clinical tissue regenerative capacity in cell injection therapy. The repression of cellular miR-34a, either due to miR-34a inhibitors or exposure to oxidative stress, unexpectedly resulted in the elevated release of miR-184 and -24-3p. Secretions of VEGF, interleukin 6, monocyte chemotactic protein-1, and MMP were all repressed in both mature CD44-/dull and degenerated CD44+++ hCEC, transfected with an miR-184 mimic. CONCLUSIONS The elevated release of miR-184 into AqH may constitute cellular interplay that prevents the aggravation of HCE degeneration induced by oxidative stress, thereby sustaining tissue homeostasis in HCE.
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Key Words
- AQP-1, aquaporin 1
- AqH, aqueous humor
- CS, culture supernatant
- Corneal endothelium degeneration
- ECD, endothelial cell density
- ER, endoplasmic reticulum
- EV, extracellular vesicle
- Extracellular vesicle
- HCE, human corneal endothelium
- IL-6, interleukin 6
- MCP-1, monocyte chemotactic protein-1
- MMP, mitochondrial membrane potential
- MiR-184
- Mitochondria metabolic homeostasis
- Oxidative stress
- SASP, senescence-associated secretory phenotype
- SLC4A11, solute carrier family 4 member 11
- SP, subpopulation
- hCEC, cultured human corneal endothelial cell
- miR, microRNA
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Affiliation(s)
- Tomoko Yamashita
- Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazuko Asada
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Morio Ueno
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Nao Hiramoto
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomoko Fujita
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Munetoyo Toda
- Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Chie Sotozono
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shigeru Kinoshita
- Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Junji Hamuro
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Wright BA, Kvansakul M, Schierwater B, Humbert PO. Cell polarity signalling at the birth of multicellularity: What can we learn from the first animals. Front Cell Dev Biol 2022; 10:1024489. [PMID: 36506100 PMCID: PMC9729800 DOI: 10.3389/fcell.2022.1024489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 10/31/2022] [Indexed: 11/25/2022] Open
Abstract
The innovation of multicellularity has driven the unparalleled evolution of animals (Metazoa). But how is a multicellular organism formed and how is its architecture maintained faithfully? The defining properties and rules required for the establishment of the architecture of multicellular organisms include the development of adhesive cell interactions, orientation of division axis, and the ability to reposition daughter cells over long distances. Central to all these properties is the ability to generate asymmetry (polarity), coordinated by a highly conserved set of proteins known as cell polarity regulators. The cell polarity complexes, Scribble, Par and Crumbs, are considered to be a metazoan innovation with apicobasal polarity and adherens junctions both believed to be present in all animals. A better understanding of the fundamental mechanisms regulating cell polarity and tissue architecture should provide key insights into the development and regeneration of all animals including humans. Here we review what is currently known about cell polarity and its control in the most basal metazoans, and how these first examples of multicellular life can inform us about the core mechanisms of tissue organisation and repair, and ultimately diseases of tissue organisation, such as cancer.
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Affiliation(s)
- Bree A. Wright
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - Marc Kvansakul
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia,Research Centre for Molecular Cancer Prevention, La Trobe University, Melbourne, VIC, Australia
| | - Bernd Schierwater
- Institute of Animal Ecology and Evolution, University of Veterinary Medicine Hannover, Foundation, Bünteweg, Hannover, Germany
| | - Patrick O. Humbert
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia,Research Centre for Molecular Cancer Prevention, La Trobe University, Melbourne, VIC, Australia,Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, VIC, Australia,Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia,*Correspondence: Patrick O. Humbert,
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Non-degradable autophagic vacuoles are indispensable for cell competition. Cell Rep 2022; 40:111292. [PMID: 36044857 DOI: 10.1016/j.celrep.2022.111292] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 04/28/2022] [Accepted: 08/10/2022] [Indexed: 12/25/2022] Open
Abstract
Cell competition is a process by which unwanted cells are eliminated from tissues. Apical extrusion is one mode whereby normal epithelial cells remove transformed cells, but it remains unclear how this process is mechanically effected. In this study, we show that autophagic and endocytic fluxes are attenuated in RasV12-transformed cells surrounded by normal cells due to lysosomal dysfunction, and that chemical manipulation of lysosomal activity compromises apical extrusion. We further find that RasV12 cells deficient in autophagy initiation machinery are resistant to elimination pressure exerted by normal cells, suggesting that non-degradable autophagic vacuoles are required for cell competition. Moreover, in vivo analysis revealed that autophagy-ablated RasV12 cells are less readily eliminated by cell competition, and remaining transformed cells destroy ductal integrity, leading to chronic pancreatitis. Collectively, our findings illuminate a positive role for autophagy in cell competition and reveal a homeostasis-preserving function of autophagy upon emergence of transformed cells.
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Hepatocyte growth factor derived from senescent cells attenuates cell competition-induced apical elimination of oncogenic cells. Nat Commun 2022; 13:4157. [PMID: 35851277 PMCID: PMC9293948 DOI: 10.1038/s41467-022-31642-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 06/24/2022] [Indexed: 11/09/2022] Open
Abstract
Cellular senescence and cell competition are important tumor suppression mechanisms that restrain cells with oncogenic mutations at the initial stage of cancer development. However, the link between cellular senescence and cell competition remains unclear. Senescent cells accumulated during the in vivo aging process contribute toward age-related cancers via the development of senescence-associated secretory phenotype (SASP). Here, we report that hepatocyte growth factor (HGF), a SASP factor, inhibits apical extrusion and promotes basal protrusion of Ras-mutated cells in the cell competition assay. Additionally, cellular senescence induced by a high-fat diet promotes the survival of cells with oncogenic mutations, whereas crizotinib, an inhibitor of HGF signaling, provokes the removal of mutated cells from mouse livers and intestines. Our study provides evidence that cellular senescence inhibits cell competition-mediated elimination of oncogenic cells through HGF signaling, suggesting that it may lead to cancer incidence during aging.
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47
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Calcium sparks enhance the tissue fluidity within epithelial layers and promote apical extrusion of transformed cells. Cell Rep 2022; 40:111078. [PMID: 35830802 DOI: 10.1016/j.celrep.2022.111078] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 05/13/2022] [Accepted: 06/20/2022] [Indexed: 11/22/2022] Open
Abstract
In vertebrates, newly emerging transformed cells are often apically extruded from epithelial layers through cell competition with surrounding normal epithelial cells. However, the underlying molecular mechanism remains elusive. Here, using phospho-SILAC screening, we show that phosphorylation of AHNAK2 is elevated in normal cells neighboring RasV12 cells soon after the induction of RasV12 expression, which is mediated by calcium-dependent protein kinase C. In addition, transient upsurges of intracellular calcium, which we call calcium sparks, frequently occur in normal cells neighboring RasV12 cells, which are mediated by mechanosensitive calcium channel TRPC1 upon membrane stretching. Calcium sparks then enhance cell movements of both normal and RasV12 cells through phosphorylation of AHNAK2 and promote apical extrusion. Moreover, comparable calcium sparks positively regulate apical extrusion of RasV12-transformed cells in zebrafish larvae as well. Hence, calcium sparks play a crucial role in the elimination of transformed cells at the early phase of cell competition.
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48
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Nichols J, Lima A, Rodríguez TA. Cell competition and the regulative nature of early mammalian development. Cell Stem Cell 2022; 29:1018-1030. [PMID: 35803224 DOI: 10.1016/j.stem.2022.06.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The mammalian embryo exhibits a remarkable plasticity that allows it to correct for the presence of aberrant cells, adjust its growth so that its size is in accordance with its developmental stage, or integrate cells of another species to form fully functional organs. Here, we will discuss the contribution that cell competition, a quality control that eliminates viable cells that are less fit than their neighbors, makes to this plasticity. We will do this by reviewing the roles that cell competition plays in the early mammalian embryo and how they contribute to ensure normal development of the embryo.
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Affiliation(s)
- Jennifer Nichols
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK.
| | - Ana Lima
- National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
| | - Tristan A Rodríguez
- National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
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DuBose CO, Daum JR, Sansam CL, Gorbsky GJ. Dynamic Features of Chromosomal Instability during Culture of Induced Pluripotent Stem Cells. Genes (Basel) 2022; 13:genes13071157. [PMID: 35885940 PMCID: PMC9318709 DOI: 10.3390/genes13071157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 06/15/2022] [Accepted: 06/21/2022] [Indexed: 02/04/2023] Open
Abstract
Induced pluripotent stem cells (iPSCs) hold great potential for regenerative medicine. By reprogramming a patient′s own cells, immunological rejection can be avoided during transplantation. For expansion and gene editing, iPSCs are grown in artificial culture for extended times. Culture affords potential danger for the accumulation of genetic aberrations. To study these, two induced pluripotent stem (iPS) cell lines were cultured and periodically analyzed using advanced optical mapping to detect and classify chromosome numerical and segmental changes that included deletions, insertions, balanced translocations and inversions. In one of the lines, a population trisomic for chromosome 12 gained dominance over a small number of passages. This appearance and dominance of the culture by chromosome 12 trisomic cells was tracked through intermediate passages by the analysis of chromosome spreads. Mathematical modeling suggested that the proliferation rates of diploid versus trisomic cells could not account for the rapid dominance of the trisomic population. In addition, optical mapping revealed hundreds of structural variations distinct from those generally found within the human population. Many of these structural variants were detected in samples obtained early in the culturing process and were maintained in late passage samples, while others were acquired over the course of culturing.
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Affiliation(s)
- Casey O. DuBose
- Cell Cycle and Cancer Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (C.O.D.); (J.R.D.)
| | - John R. Daum
- Cell Cycle and Cancer Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (C.O.D.); (J.R.D.)
| | - Christopher L. Sansam
- Cell Cycle and Cancer Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (C.O.D.); (J.R.D.)
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Gary J. Gorbsky
- Cell Cycle and Cancer Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (C.O.D.); (J.R.D.)
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Correspondence:
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Marongiu F, DeGregori J. The sculpting of somatic mutational landscapes by evolutionary forces and their impacts on aging-related disease. Mol Oncol 2022; 16:3238-3258. [PMID: 35726685 PMCID: PMC9490148 DOI: 10.1002/1878-0261.13275] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/29/2022] [Accepted: 05/19/2022] [Indexed: 12/19/2022] Open
Abstract
Aging represents the major risk factor for the development of cancer and many other diseases. Recent findings show that normal tissues become riddled with expanded clones that are frequently driven by cancer‐associated mutations in an aging‐dependent fashion. Additional studies show how aged tissue microenvironments promote the initiation and progression of malignancies, while young healthy tissues actively suppress the outgrowth of malignant clones. Here, we discuss conserved mechanisms that eliminate poorly functioning or potentially malignant cells from our tissues to maintain organismal health and fitness. Natural selection acts to preserve tissue function and prevent disease to maximize reproductive success but these mechanisms wane as reproduction becomes less likely. The ensuing age‐dependent tissue decline can impact the shape and direction of clonal somatic evolution, with lifestyle and exposures influencing its pace and intensity. We also consider how aging‐ and exposure‐dependent clonal expansions of “oncogenic” mutations might both increase cancer risk late in life and contribute to tissue decline and non‐malignant disease. Still, we can marvel at the ability of our bodies to avoid cancers and other diseases despite the accumulation of billions of cells with cancer‐associated mutations.
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Affiliation(s)
- Fabio Marongiu
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,Department of Biomedical Sciences, Section of Pathology, University of Cagliari, Italy
| | - James DeGregori
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,University of Colorado Comprehensive Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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