In situ bone regeneration and vertical bone augmentation have been huge problems in clinical practice, always imposing a significant economic burden and causing patient suffering. Herein, MgZnYNd magnesium alloy rod implantation in mouse femur resulted in substantial subperiosteal new bone formation, with osteoimmunomodulation playing a pivotal role. Abundant macrophages were attracted to the subperiosteal new bone region and proved to be the most important regulation cells for bone regeneration. Periosteum stripping, macrophage depletion, and interleukin-10 (IL-10) blockade effectively diminished the MgZnYNd alloy-induced subperiosteal osteogenesis. Mechanistically, the degradation products of MgZnYNd alloy promoted M2 macrophage polarization and the secretion of anti-inflammatory cytokine IL-10, which enhanced periosteum-derived stem cells (PDSCs) osteogenesis through the JAK1-STAT3 pathway. An anti-IL-10 neutralizing antibody or STAT3 inhibitor significantly inhibited M2 macrophage-mediated osteogenic differentiation of PDSCs. Transcriptomics and proteomics revealed that periostin is the core regulator of PDSCs osteogenic differentiation. Furthermore, a novel clinical translation application of Mg-induced subperiosteal osteogenesis was developed, demonstrating its ability to preserve the height and width of the alveolar crest in rats and rabbits following tooth extraction. Collectively, these findings unveil a previously undefined role for Mg alloy-induced subperiosteal osteogenesis via macrophage-mediated osteoimmunomodulation, suggesting the therapeutic potential of magnesium alloy in bone regeneration and bone augmentation.

Renal cell carcinoma (RCC) is among the most frequently occurring types of cancer, and its metastasis is a major contributor to its elevated mortality. Before the primary tumor metastasizes to secondary or distant organs, it remodels the microenvironment of these sites, creating a pre-metastatic niche (PMN) conducive to the colonization and growth of metastatic tumors. RCC releases a variety of biomolecules that induce angiogenesis, alter vascular permeability, modulate immune cells to create an immunosuppressive microenvironment, affect extracellular matrix remodeling and metabolic reprogramming, and determine the organotropism of metastasis through different signaling pathways. This review summarizes the principal processes and mechanisms underlying the formation of the premetastatic niche in RCC. Additionally, we emphasize the significance and potential of targeting PMNs for the prevention and treatment of tumor metastasis in future therapeutic approaches. Finally, we summarized the currently potential targeted strategies for detecting and treating PMN in RCC and provide a roadmap for further in-depth studies on PMN in RCC.

Over the last 2 decades, research has increasingly focused on cancer stem cells (CSCs), considered responsible for tumor formation, resistance to therapies, and relapse. The traditional "static" CSC model used to describe tumor heterogeneity has been challenged by the evidence of CSC dynamic nature and plasticity. A comprehensive understanding of the mechanisms underlying this plasticity, and the capacity to unambiguously identify cancer markers to precisely target CSCs are crucial aspects for advancing cancer research and introducing more effective treatment strategies. In this context, Raman spectroscopy (RS) and specific Raman schemes, including CARS, SRS, SERS, have emerged as innovative tools for molecular analyses both in vitro and in vivo. In fact, these techniques have demonstrated considerable potential in the field of cancer detection, as well as in intraoperative settings, thanks to their label-free nature and minimal invasiveness. However, the RS integration in pre-clinical and clinical applications, particularly in the CSC field, remains limited. This review provides a concise overview of the historical development of RS and its advantages. Then, after introducing the CSC features and the challenges in targeting them with traditional methods, we review and discuss the current literature about the application of RS for revealing and characterizing CSCs and their inherent plasticity, including a brief paragraph about the integration of artificial intelligence with RS. By providing the possibility to better characterize the cellular diversity in their microenvironment, RS could revolutionize current diagnostic and therapeutic approaches, enabling early identification of CSCs and facilitating the development of personalized treatment strategies.

Stem cells have emerged as a pivotal area of research in the field of oncology, offering new insights into the mechanisms of cancer initiation, progression, and resistance to therapy. This review provides a comprehensive overview of the role of stem cells in cancer, focusing on cancer stem cells (CSCs), their characteristics, and their implications for cancer therapy. We discuss the origin and identification of CSCs, their role in tumorigenesis, metastasis, and drug resistance, and the potential therapeutic strategies targeting CSCs. Additionally, we explore the use of normal stem cells in cancer therapy, focusing on their role in tissue regeneration and their use as delivery vehicles for anticancer agents. Finally, we highlight the challenges and future directions in stem cell research in cancer.

These findings provide a critical first step in characterizing the capacity of OS-derived exosomes to reprogram primary LFs toward a tumor-promoting inflammatory phenotype in vitro, offering novel molecular targets for the modulation of fibroblasts in the lung microenvironment as potential therapeutic strategies to prevent OS metastasis.

Cancer metastasis is a complicated biological process that critically affects cancer progression, patient outcomes, and treatment plans. A significant step in metastasis is the formation of a pre-metastatic niche (PMN). A small subset of cells within tumors, known as cancer stem cells (CSCs), possess unique characteristics including, differentiation into different cell types within the tumor, self-renewal, and resistance to conventional therapies, that enable them to initiate tumors and drive metastasis. PMN plays an important role in preparing secondary organs for the arrival and proliferation of CSCs, thereby facilitating metastasis. CSC-derived exosomes are crucial components in the complex interplay between CSCs and the tumor microenvironment. These exosomes function as transporters of various substances that can promote cancer progression, metastasis, and modulation of pre-metastatic environments by delivering microRNA (miRNA, miR) cargo. This review aims to illustrate how exosomal miRNAs (exo-miRs) secreted by CSCs can predispose PMN and promote angiogenesis and metastasis.

Psychological stress causes gut microbial dysbiosis and cancer progression, yet how gut microbiota determines psychological stress-induced tumor development remains unclear. Here we showed that psychological stress promotes breast tumor growth and cancer stemness, an outcome that depends on gut microbiota in germ-free and antibiotic-treated mice. Metagenomic and metabolomic analyses revealed that psychological stress markedly alters the composition and abundance of gut microbiota, especially Akkermansia muciniphila (A. muciniphila), and decreases short-chain fatty acid butyrate. Supplement of active A. muciniphila, butyrate or a butyrate-producing high fiber diet dramatically reversed the oncogenic property and anxiety-like behavior of psychological stress in a murine spontaneous tumor model or an orthotopic tumor model. Mechanistically, RNA sequencing analysis screened out that butyrate decreases LRP5 expression to block the activation of Wnt/β-catenin signaling pathway, dampening breast cancer stemness. Moreover, butyrate as a HDAC inhibitor elevated histone H3K9 acetylation level to transcriptionally activate ZFP36, which further accelerates LRP5 mRNA decay by binding adenine uridine-rich (AU-rich) elements of LRP5 transcript. Clinically, fecal A. muciniphila and serum butyrate were inversely correlated with tumoral LRP5/β-catenin expression, poor prognosis and negative mood in breast cancer patients. Altogether, our findings uncover a microbiota-dependent mechanism of psychological stress-triggered cancer stemness, and provide both clinical biomarkers and potential therapeutic avenues for cancer patients undergoing psychological stress.

Cancer-associated fibroblasts (CAFs) play a pivotal role in cancer progression, including mediating tumour cell invasion via their pro-invasive secretory profile and ability to remodel the extracellular matrix (ECM). Given that reduced CAF abundance in tumours correlates with improved outcomes in various cancers, we set out to identify epigenetic targets involved in CAF activation in regions of tumour-stromal mixing with the goal of reducing tumour aggressiveness. Using the GLAnCE (Gels for Live Analysis of Compartmentalized Environments) platform, we performed an image-based, phenotypic screen that enabled us to identify modulators of CAF abundance and the capacity of CAFs to induce tumour cell invasion. We identified EHMT2 (also known as G9a), an enzyme that targets the methylation of histone 3 lysine 9 (H3K9), as a potent modulator of CAF abundance and CAF-mediated tumour cell invasion. Transcriptomic and functional analysis of EHMT2-inhibited CAFs revealed EHMT2 participated in driving CAFs towards a pro-invasive phenotype and mediated CAF hyperproliferation, a feature typically associated with activated fibroblasts in tumours. Our study suggests that EHMT2 regulates CAF state within the tumour microenvironment by impacting CAF activation, as well as by magnifying the pro-invasive effects of these activated CAFs on tumour cell invasion through promoting CAF hyperproliferation.

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME). Given their various roles in tumor progression and treatment resistance, CAFs are promising therapeutic targets in cancer. The elimination of tumor-promoting CAFs has been investigated in various animal models to determine whether it effectively suppresses tumor growth. Based on recent evidence, several simple strategies have been proposed to eliminate tumor-promoting CAFs and attenuate these features. In addition, attention has focused on the critical role that CAFs play in the immunosuppressive TME. Therefore, the functional reprogramming of CAFs in combination with immune checkpoint inhibitors has also been investigated as a possible therapeutic approach. However, although potential targets in CAFs have been widely characterized, the plasticity and heterogeneity of CAFs complicate the understanding of their properties and present difficulties for clinical application. Moreover, the identification of tumor-suppressive CAFs highlights the necessity for the development of therapeutic approaches that can distinguish and switch between tumor-promoting and tumor-suppressive CAFs in an appropriate manner. In this review, we introduce the origins and diversity of CAFs, their role in cancer, and current therapeutic strategies aimed at targeting CAFs, including ongoing clinical evaluations.

Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.

Oral squamous cell carcinoma (OSCC) is frequently observed as the predominant malignancy affecting the oral cavity, with distant metastasis greatly affecting the treatment and long-term outlook for individuals with OSCC. Immune checkpoint inhibitors are a highly promising cancer treatment strategy currently available, but they are only successful for a small fraction of individuals with OSCC. Due to the insufficient understanding of the immune escape mechanisms in OSCC, coupled with disappointing treatment outcomes for patients with highly heterogeneous metastatic diseases, there is an urgent need for further exploration of immune target therapy strategies. This review discusses the mechanisms by which OSCC cells evade immune surveillance and attack, focusing on four aspects: metastasis-initiating cells, increased immune suppression, immune escape of dormant cells, and immune stromal crosstalk during metastasis. Additionally, we explore new areas in immune therapy for OSCC. In summary, our investigation offers fresh perspectives on the relationship between the tumor microenvironment and immune molecules, highlighting the importance of overcoming immune evasion for the development of novel therapies to manage OSCC metastasis and enhance patient outcomes.

The progression of malignant tumors leads to the development of secondary tumors in various organs, including bones, the brain, liver, and lungs. This metastatic process severely impacts the prognosis of patients, significantly affecting their quality of life and survival rates. Research efforts have consistently focused on the intricate mechanisms underlying this process and the corresponding clinical management strategies. Consequently, a comprehensive understanding of the biological foundations of tumor metastasis, identification of pivotal signaling pathways, and systematic evaluation of existing and emerging therapeutic strategies are paramount to enhancing the overall diagnostic and treatment capabilities for metastatic tumors. However, current research is primarily focused on metastasis within specific cancer types, leaving significant gaps in our understanding of the complex metastatic cascade, organ-specific tropism mechanisms, and the development of targeted treatments. In this study, we examine the sequential processes of tumor metastasis, elucidate the underlying mechanisms driving organ-tropic metastasis, and systematically analyze therapeutic strategies for metastatic tumors, including those tailored to specific organ involvement. Subsequently, we synthesize the most recent advances in emerging therapeutic technologies for tumor metastasis and analyze the challenges and opportunities encountered in clinical research pertaining to bone metastasis. Our objective is to offer insights that can inform future research and clinical practice in this crucial field.

Cancer stem cells (CSCs) are a small subset within the tumor mass significantly contributing to cancer progression through dysregulation of various oncogenic pathways, driving tumor growth, chemoresistance and metastasis formation. The aggressive behavior of CSCs is guided by several intracellular signaling pathways such as WNT, NF-kappa-B, NOTCH, Hedgehog, JAK-STAT, PI3K/AKT1/MTOR, TGF/SMAD, PPAR and MAPK kinases, as well as extracellular vesicles such as exosomes, and extracellular signaling molecules such as cytokines, chemokines, pro-angiogenetic and growth factors, which finely regulate CSC phenotype. In this scenario, tumor microenvironment (TME) is a key player in the establishment of a permissive tumor niche, where CSCs engage in intricate communications with diverse immune cells. The "oncogenic" immune cells are mainly represented by B and T lymphocytes, NK cells, and dendritic cells. Among immune cells, macrophages exhibit a more plastic and adaptable phenotype due to their different subpopulations, which are characterized by both immunosuppressive and inflammatory phenotypes. Specifically, tumor-associated macrophages (TAMs) create an immunosuppressive milieu through the production of a plethora of paracrine factors (IL-6, IL-12, TNF-alpha, TGF-beta, CCL1, CCL18) promoting the acquisition by CSCs of a stem-like, invasive and metastatic phenotype. TAMs have demonstrated the ability to communicate with CSCs via direct ligand/receptor (such as CD90/CD11b, LSECtin/BTN3A3, EPHA4/Ephrin) interaction. On the other hand, CSCs exhibited their capacity to influence immune cells, creating a favorable microenvironment for cancer progression. Interestingly, the bidirectional influence of CSCs and TME leads to an epigenetic reprogramming which sustains malignant transformation. Nowadays, the integration of biological and computational data obtained by cutting-edge technologies (single-cell RNA sequencing, spatial transcriptomics, trajectory analysis) has significantly improved the comprehension of the biunivocal multicellular dialogue, providing a comprehensive view of the heterogeneity and dynamics of CSCs, and uncovering alternative mechanisms of immune evasion and therapeutic resistance. Moreover, the combination of biology and computational data will lead to the development of innovative target therapies dampening CSC-TME interaction. Here, we aim to elucidate the most recent insights on CSCs biology and their complex interactions with TME immune cells, specifically TAMs, tracing an exhaustive scenario from the primary tumor to metastasis formation.

Eliminating cancer stem cells (CSCs) is essential for the effective treatment of triple-negative breast cancer (TNBC). This study synthesized Au@cerium-zinc composite core@shell nanoparticles (Au@Zn/CeO) that were subsequently conjugated with Escherichia coli (E. coli) to create the engineered bacterium AZCE, which was then combined with microneedle carriers and freeze-dried to obtain AZCE-MN. Upon implantation into TNBC tumors, the inherent properties of E. coli facilitate AZCE to penetrate the extracellular matrix and break through the basement membrane, enabling effective delivery of AZC to CSCs-enriched regions deep within the tumor. The released Zn2+ induces mitochondrial dysfunction and amplifies reactive oxygen species (ROS) production. The redox cycling between Ce3+/Ce4+ effectively depleted glutathione, which further increased ROS generation. Under near-infrared laser irradiation, Au nanorods initiated photothermal therapy, effectively ablating CSCs while amplifying catalytic reactions and ionic effects. This microneedle-mediated engineered bacteria delivery improved nanodrug penetration in tumor tissues, providing new insights for TNBC clinical treatment.

The tree shrew brain has garnered considerable attention due to its remarkable similarities to human brain. However, the cellular composition and genetic signatures of tree shrew hippocampus across postnatal life remain poorly characterized. Here, we establish the first single-nucleus transcriptomic atlas of tree shrew hippocampus spanning postnatal life, detailing the dynamics and diversity of the neurogenic lineage, oligodendrocytes, microglia, and endothelial cells. Notably, cross-species transcriptomic comparison among humans, macaques, tree shrews, and mice reveals that the tree shrew transcriptome resembles that of macaques, making it a promising model for simulating human neurological diseases. More interestingly, we identified a unique class of tree shrew-specific neural stem cells and established SOX6, ADAMTS19, and MAP2 as their markers. Furthermore, aberrant gene expression and cellular dysfunction in the tree shrew hippocampus are linked to neuroinflammation and cognitive impairment during tree shrew aging. Our study provides extensive resources on cell composition and transcriptomic profiles, serving as a foundation for future research on neurodevelopmental and neurological disorders in tree shrews.

Hypoxia can weaken the efficacy of radiotherapy and decrease tumor immunogenicity leading to immune escape. Thus, a thorough understanding of the key signaling pathways regulated by hypoxia is vitally important to enhance the radiosensitivity and improve immunosuppressive microenvironment of glioma. In this study, we verified the crucial role of hypoxia-inducible gene 2 (HIG-2) in lipid droplet (LD) accumulation and demonstrated that HIG-2 binding to frizzled class receptor 10 (FZD10) activated Wnt/β-catenin signaling pathway and increased its downstream insulin-like growth factor binding protein 2 (IGFBP2) level in microparticles (MPs) derived from glioma stem cells (GSCs), leading to decreased radiosensitivity and immunogenicity of MPs-receiving cells via the cross-talk between GSCs and non-stem glioma cells (GCs). These findings suggest that HIG-2 may be a promising target in glioma radiotherapy and/or immunotherapy.

Identifying patients at risk for metastatic relapse is a critical medical need. We identified a common missense germline variant in proprotein convertase subtilisin/kexin type 9 (PCSK9) (rs562556, V474I) that is associated with reduced survival in multiple breast cancer patient cohorts. Genetic modeling of this gain-of-function single-nucleotide variant in mice revealed that it causally promotes breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and enhanced metastatic proliferative competence by targeting tumoral low-density lipoprotein receptor related protein 1 (LRP1) receptors, which repressed metastasis-promoting genes XAF1 and USP18. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. In a large Swedish early-stage breast cancer cohort, rs562556 homozygotes had a 22% risk of distant metastatic relapse at 15 years, whereas non-homozygotes had a 2% risk. Our findings reveal that a commonly inherited genetic alteration governs breast cancer metastasis and predicts survival-uncovering a hereditary basis underlying breast cancer metastasis.

Metastasis causes most cancer deaths and reflects transitions from primary tumor escape to seeding and growth at metastatic sites. Epithelial-to-mesenchymal transition (EMT) is important early in metastasis to enable cancer cells to detach from neighboring cells, become migratory, and escape the primary tumor. While different phases of metastasis expose cells to variable nutrient environments and demands, the metabolic requirements and plasticity of each step are uncertain. Here we show that EMT and primary tumor escape are stimulated by disrupted oxidative metabolism. Using Renal Cell Carcinoma (RCC) patient samples, we identified the mitochondrial electron transport inhibitor NDUFA4L2 as upregulated in cells undergoing EMT. Deletion of NDUFA4L2 enhanced oxidative metabolism and prevented EMT and metastasis while NDUFA4L2 overexpression enhanced these processes. Mechanistically, NDUFA4L2 suppressed oxidative phosphorylation and caused citric acid cycle intermediates to accumulate, which modified chromatin accessibility of EMT-related loci to drive primary tumor escape. The effect of impaired mitochondrial metabolism to drive EMT appeared general, as renal cell carcinoma patient tumors driven by fumarate hydratase mutations with disrupted oxidative phosphorylation were highly metastatic and also had robust EMT. These findings highlight the importance of dynamic shifts in metabolism for cell migration and metastasis, with mitochondrial impairment driving early phases of this process. Understanding mitochondrial dynamics may have important implications in both basic and translational efforts to prevent cancer deaths.

Metastasis is the primary cause of mortality in small cell lung cancer (SCLC), with the liver being a predominant site for distal metastasis. Despite this clinical significance, mechanisms underlying the interaction between SCLC and liver microenvironment, fostering metastasis, remain unclear.

SCLC patient tissue array, bioinformatics analysis were performed to demonstrate the role of periostin (POSTN) in SCLC progression, metastasis, and prognosis. Cell migration, invasion and sphere formation assay were performed to determine the oncogenic role of POSTN. RNA sequencing analysis was utilized to identify the key signaling pathway regulated by POSTN. Immunoprecipitation, immunofluorescence and co-culture system were used to clarify the mechanism of POSTN-NOTCH1 axis in tumor cells-hepatic stellate cells (HSCs) crosstalk. Subcutaneous xenograft model and liver metastasis model were established to examine the anti-tumor growth and metastases effect of targeting POSTN-NOTCH1 signaling axis.

Elevated expression of POSTN in SCLC is correlated with accelerated tumor progression and metastasis. Conditioned medium rich in POSTN derived from SCLC tumors demonstrates the ability to activate HSCs in the liver microenvironment. Mechanistically, POSTN emerges as a binding partner for the membrane receptor NOTCH1 and transducing the extracellular signals to intracellular fibroblasts. Furthermore, targeting the POSTN-NOTCH1 signaling axis proves effective in suppressing SCLC tumor growth and inhibiting liver metastasis. This study elucidates that the SCLC-derived secreted protein POSTN interacts with NOTCH1 on HSCs to promote the activation of HSCs, thereby providing a favorable microenvironment for liver metastasis.

These findings uncover the intricate communications between primary SCLC cells and HSCs in the tumor microenvironment mediated by the secreted protein POSTN in the context of liver metastasis. Consequently, targeting the POSTN-NOTCH1 signaling axis emerges as a promising therapeutic strategy for metastatic SCLC.

Recent evidence has revealed that cancer is not solely driven by genetic abnormalities but also by significant metabolic dysregulation. Cancer cells exhibit altered metabolic demands and rewiring of cellular metabolism to sustain their malignant characteristics. Metabolic reprogramming has emerged as a hallmark of cancer, playing a complex role in breast cancer initiation, progression, and metastasis. The different molecular subtypes of breast cancer exhibit distinct metabolic genotypes and phenotypes, offering opportunities for subtype-specific therapeutic approaches. Cancer-associated metabolic phenotypes encompass dysregulated nutrient uptake, opportunistic nutrient acquisition strategies, altered utilization of glycolysis and TCA cycle intermediates, increased nitrogen demand, metabolite-driven gene regulation, and metabolic interactions with the microenvironment. The tumor microenvironment, consisting of stromal cells, immune cells, blood vessels, and extracellular matrix components, influences metabolic adaptations through modulating nutrient availability, oxygen levels, and signaling pathways. Metastasis, the process of cancer spread, involves intricate steps that present unique metabolic challenges at each stage. Successful metastasis requires cancer cells to navigate varying nutrient and oxygen availability, endure oxidative stress, and adapt their metabolic processes accordingly. The metabolic reprogramming observed in breast cancer is regulated by oncogenes, tumor suppressor genes, and signaling pathways that integrate cellular signaling with metabolic processes. Understanding the metabolic adaptations associated with metastasis holds promise for identifying therapeutic targets to disrupt the metastatic process and improve patient outcomes. This chapter explores the metabolic alterations linked to breast cancer metastasis and highlights the potential for targeted interventions in this context.

Macrophages that acquire an immunosuppressive phenotype play a crucial role in establishing the pre-metastatic niche (PMN), which is essential for facilitating breast cancer metastasis to distant organs. Our study showed that increased activity of the aryl hydrocarbon receptor (AHR) in lung macrophages plays a crucial role in establishing the immunosuppressive PMN in breast cancer. Specifically, AHR activation led to high expression of PD-L1 on macrophages by directly binding to the promoter of Pdl1. This upregulation of PD-L1 promoted the differentiation of regulatory T cells (Tregs) within the PMN, further enhancing immunosuppressive conditions. Mice with Ahr conditional deletion in macrophages had reduced lung metastasis of breast cancer. The elevated AHR levels in PMN macrophages were induced by GM-CSF, which was secreted by breast cancer cells. Mechanistically, the activated STAT5 signaling pathway induced by GM-CSF prevented AHR from being ubiquitinated, thereby sustaining its activity in macrophages. In breast cancer patients, the expression of AHR and PD-L1 was correlated with increased Treg cell infiltration, and higher levels of AHR were associated with a poor prognosis. These findings reveal that the crosstalk of breast cancer cells, lung macrophages, and Treg cells via the GM-CSF-STAT5-AHR-PD-L1 cascade modulates the lung pre-metastatic niche during breast cancer progression.

Metastasis is the main cause of cancer-related deaths. The formation and growth of metastasis is a multistep process. Tumor cells extravasating in the secondary organ are in contact with a new microenvironment and a new extracellular matrix (ECM), called the metastatic niche. Some components of the ECM, such as periostin, can induce tumor cell growth in macrometastasis. In contrast, other components, such as Thrombospondin 1 (TSP-1), can maintain isolated cells in a dormant state. During dormancy, intracellular signaling activation, such as p38, maintains tumor cells arrested in the cell-cycle G0 phase for years. At any moment, stress can induce ECM modifications and binding to their specific receptors (mainly integrins) and reactivate dormant tumor cell growth in macrometastasis. In this review, we describe the tumor microenvironment of the different niches implicated in tumor cell dormancy. The role of ECM components and their associated receptors and intracellular signaling in the reactivation of dormant tumor cells in macrometastasis will be emphasized. We also present the different methodologies and experimental approaches used to study tumor cell dormancy. Finally, we discuss the current and future treatment strategies to avoid late metastasis relapse in patients.

From their early genesis, tumour cells integrate with the surrounding normal cells to form an abnormal structure that is tightly integrated with the host organism via blood and lymphatic vessels and even neural associations. Using these connections, emerging cancers send a plethora of mediators that efficiently perturb the entire organism and induce changes in distant tissues. These perturbations serendipitously favour early metastatic establishment by promoting a more favourable tissue environment (niche) that supports the persistence of disseminated tumour cells within a foreign tissue. Because the establishment of early metastatic niches represents a key limiting step for metastasis, the creation of a more suitable pre-conditioned tissue strongly enhances metastatic success. In this Review, we provide an updated view of the mechanisms and mediators of primary tumours described so far that induce a pro-metastatic conditioning of distant organs, which favours early metastatic niche formation. We reflect on the nature of cancer-induced systemic conditioning, considering that non-cancer-dependent perturbations of tissue homeostasis are also able to trigger pro-metastatic conditioning. We argue that a more holistic view of the processes catalysing metastatic progression is needed to identify preventive or therapeutic opportunities.

Triple-negative breast cancer (TNBC) lacks the expression of hormone and HER2 receptors and is highly malignant with no effective therapeutic targets. In TNBC, the cancer stem-like cell (CSC) population is considered to be the main cause of resistance to treatment. Thus, the therapeutic targeting of this population could substantially improve patient survival. Here, we identify the RNA-binding protein ZCCHC24 as enriched in the mesenchymal-like TNBC population. ZCCHC24 promotes the expression of a set of genes related to tumorigenicity and treatment resistance by directly binding to the cis-element "UGUWHWWA" in their mRNAs, thereby stabilizing them. One of the ZCCHC24 targets, ZEB1, is a transcription factor that promotes the expression of cancer stemness genes and reciprocally induces ZCCHC24 expression. ZCCHC24 knockdown by siRNAs shows a therapeutic effect and reduces the mesenchymal-like cell population in TNBC patient-derived xenografts. ZCCHC24 knockdown also has additive effects with the BET inhibitor JQ1 in suppressing tumor growth in TNBC patient-derived xenografts.

The tumor microenvironment (TME) is a dynamic and complex medium that plays a central role in cancer progression, metastasis, and treatment resistance. Among the key elements of the TME, cancer-associated fibroblasts (CAFs) are particularly important for their ability to remodel the extracellular matrix, promote angiogenesis, and suppress anti-tumor immune responses. Fibroblast activation protein (FAP), predominantly expressed by CAFs, has emerged as a promising target in both cancer diagnostics and therapeutics. In nuclear medicine, targeting FAP offers new opportunities for non-invasive imaging using radiolabeled fibroblast activation protein inhibitors (FAPIs). These FAP-specific radiotracers have demonstrated excellent tumor detection properties compared to traditional radiopharmaceuticals such as [18F]FDG, especially in cancers with low metabolic activity, like liver and biliary tract tumors. The most recent FAPI derivatives not only enhance the accuracy of positron emission tomography (PET) imaging but also hold potential for theranostic applications by delivering targeted radionuclide therapies. This review examines the biological underpinnings of FAP in the TME, the design of FAPI-based imaging agents, and their evolving role in cancer diagnostics, highlighting the potential of FAP as a target for precision oncology.

Triple-negative breast cancer (TNBC) is the deadliest subtype of breast cancer (BC). Tumor-derived extracellular vesicles (EVs) trigger tumor progression by promoting M2 polarization. Some lncRNAs can be encapsulated into EVs for intercellular communication. Herein, we investigated the mechanism of TNBC-derived EV-shuttled lncRNA MALAT1 on macrophage polarization/tumorigenesis.

BC-associated targeted EV-derived lncRNAs were screened. Tumor tissues/tissues adjacent to cancer of TNBC patients, and blood samples of all subjects were collected. MALAT1/POSTN mRNA levels in tumor tissues/tissues adjacent to cancer, and MALAT1 expression in EVs and its correlation with TNBC patient overall survival were assessed by RT-qPCR/Kaplan-Meier survival analysis/log-rank test. TNBC patient M2 infiltration was detected by flow cytometry. MALAT1/POSTN levels in EVs/macrophages were regulated by transfection. Hippo/YAP activation was determined by Western blot. Nude mouse xenograft model was established and metastasis was detected by H&E staining.

MALAT1/POSTN were up-regulated and correlated with M2 infiltration/poor prognosis in TNBC patients. TNBC-derived EVs induced M2 polarization. MALAT1 was highly expressed in TNBC-derived EVs and could be transferred to macrophages via EVs to induce M2 polarization. POSTN overexpression diminished the inhibitory effect of MALAT1 knockdown on M2 markers. EVs activated the Hippo/YAP pathway in macrophages. The Hippo/YAP pathway inhibition abrogated the effect of POSTN overexpression on M2 marker expression. TNBC-EV-derived MALAT1 facilitated M2 polarization, and thus promoting occurrence and metastasis of TNBC in vitro and in vivo.

TNBC-EV-derived MALAT1 activated the Hippo/YAP axis by up-regulating POSTN, thereby inducing M2 polarization to promote TNBC occurrence and metastasis in vivo.

Tumor metastasis is a major threat to cancer patient survival. The organ-specific niche plays a pivotal role in tumor organotropic metastasis. Fibroblasts serve as a vital component of the metastatic microenvironment, but how heterogeneous metastasis-associated fibroblasts (MAFs) promote organotropic metastasis is poorly characterized. Here, we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer.

Mouse models of breast cancer pulmonary metastasis were established using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung. Single-cell RNA-sequencing (scRNA-seq) was employed to investigate the heterogeneity of MAFs. Transgenic mice were used to examine the contribution of tryptophan 2,3-dioxygenase-positive matrix fibroblasts (TDO2+ MFs) in lung metastasis.

We uncovered 3 subtypes of MAFs in the lung metastatic microenvironment, and their transcriptome profiles changed dynamically as lung metastasis evolved. As the predominant subtype, MFs were exclusively marked by platelet-derived growth factor receptor alpha (PDGFRA) and mainly located on the edge of the metastasis, and T cells were enriched around MFs. Notably, high MF signatures were significantly associated with poor survival in breast cancer patients. Lung metastases were markedly diminished, and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse models. We found that TDO2+ MFs controlled pulmonary metastasis by producing kynurenine (KYN), which upregulated ferritin heavy chain 1 (FTH1) level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2+ MF-secreted chemokines C-C motif chemokine ligand 8 (CCL8) and C-C motif chemokine ligand 11 (CCL11) recruited T cells. TDO2+ MF-derived KYN induced T cell dysfunction. Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation.

Our study reveals crucial roles of TDO2+ MFs in promoting lung metastasis and DTCs' immune evasion in the metastatic niche. It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.

ATF6 intervention reduces colorectal cancer cell and organoid viability by interrupting dysregulated Wnt signaling, identifying a novel facilitator and potential therapeutic target in colorectal cancer.

We describe the fibrotic rim formed in the desmoplastic histopathologic growth pattern (DHGP) of colorectal cancer liver metastasis (CLM) using in situ sequencing (ISS). The origin of the desmoplastic rim is still a matter of debate, and the detailed cellular organization has not yet been fully elucidated. Understanding the biology of the DHGP in CLM can lead to targeted treatment and improve survival.

We used ISS, targeting 150 genes, to characterize the desmoplastic rim by unsupervised clustering of gene coexpression patterns. The cohort comprised 10 chemo-naïve liver metastasis resection samples with a DHGP.

Unsupervised clustering of spatially mapped genes revealed molecular and cellular diversity within the desmoplastic rim. We confirmed the presence of the ductular reaction and cancer-associated fibroblasts. Importantly, we discovered angiogenesis and outer and inner zonation in the rim, characterized by nerve growth factor receptor and periostin expression.

ISS enabled the analysis of the cellular organization of the fibrous rim surrounding CLM with a DHGP and suggests a transition from the outer part of the rim, with nonspecific liver injury response, into the inner part, with gene expression indicating collagen synthesis and extracellular matrix remodeling influenced by the interaction with cancer cells, creating a cancer cell-supportive environment. Moreover, we found angiogenic processes in the rim. Our results provide a potential explanation of the origin of the rim in DHGP and lead to exploring novel targeted treatments for patients with CLM to improve survival.

A key step for metastatic outgrowth involves the generation of a deeply altered microenvironment (niche) that supports the malignant behavior of cancer cells. The complexity of the metastatic niche has posed a significant challenge in elucidating the underlying programs driving its origin. Here, by focusing on early stages of breast cancer metastasis to the lung in mice, we describe a cancer-dependent chromatin remodeling and activation of developmental programs in alveolar type 2 (AT2) cells within the niche. We show that metastatic cells can prime AT2 cells into a reprogrammed multilineage state. In turn, this cancer-induced reprogramming of AT2 cells promoted stem-like features in cancer cells and enhanced their initiation capacity. In conclusion, we propose the concept of "reflected stemness" as an early phenomenon during metastatic niche initiation, wherein metastatic cells reprogram the local tissue into a stem-like state that enhances intrinsic cancer-initiating potential, creating a positive feedback loop where tumorigenic programs are amplified.

Despite a critical role for tumor-initiating cancer stem cells (CSCs) in breast cancer progression, major questions remain about the properties and signaling pathways essential for their function. Recent discoveries highlighting mechanisms of CSC-resistance to the stress caused by chromosomal instability (CIN) may provide valuable new insight into the underlying forces driving stemness properties. While stress tolerance is a well-known attribute of CSCs, CIN-induced stress is distinctive since levels appear to increase during tumor initiation and metastasis. These dynamic changes in CIN levels may serve as a barrier constraining the effects of non-CSCs and shaping the stemness landscape during the early stages of disease progression. In contrast to most other stresses, CIN can also paradoxically activate pro-tumorigenic antiviral signaling. Though seemingly contradictory, this may indicate that mechanisms of CIN tolerance and pro-tumorigenic inflammatory signaling closely collaborate to define the CSC state. Together, these unique features may form the basis for a critical relationship between CIN and stemness properties.

Metastasis is the leading cause of cancer-related deaths. It is unclear how intratumor heterogeneity (ITH) contributes to metastasis and how metastatic cells adapt to distant tissue environments. The study of these adaptations is challenged by the limited access to patient material and a lack of experimental models that appropriately recapitulate ITH. To investigate metastatic cell adaptations and the contribution of ITH to metastasis, we analyzed single-cell transcriptomes of matched primary tumors and metastases from patient-derived xenograft models of breast cancer. We found profound transcriptional differences between the primary tumor and metastatic cells. Primary tumors upregulated several metabolic genes, whereas motility pathway genes were upregulated in micrometastases, and stress response signaling was upregulated during progression. Additionally, we identified primary tumor gene signatures that were associated with increased metastatic potential and correlated with patient outcomes. Immune-regulatory control pathways were enriched in poorly metastatic primary tumors, whereas genes involved in epithelial-mesenchymal transition were upregulated in highly metastatic tumors. We found that ITH was dominated by epithelial-mesenchymal plasticity (EMP), which presented as a dynamic continuum with intermediate EMP cell states characterized by specific genes such as CRYAB and S100A2. Elevated expression of an intermediate EMP signature correlated with worse patient outcomes. Our findings identified inhibition of the intermediate EMP cell state as a potential therapeutic target to block metastasis.

Many tumors prefer to metastasize to bone, but the underlying mechanisms remain elusive. The human skeletal system has unique physical properties, that are distinct from other organs, which play a key role in directing the behavior of tumor cells within bone. Understanding the physical journey of tumor cells within bone is crucial. In this review we discuss bone metastasis in the context of how physical cues in the bone vasculature and bone marrow niche regulate the fate of tumor cells. Our objective is to inspire innovative diagnostic and therapeutic approaches for bone metastasis from a mechanobiological perspective.

Periostin (POSTN) is a type of matrix protein that functions by binding to other matrix proteins, cell surface receptors, or other molecules, such as cytokines and proteases. POSTN has four major splicing variants (PN1-4), which are primarily expressed in fibroblasts and cancer. We have reported that we should inhibit pathological POSTN (PN1-3), but not physiological POSTN (PN4). In particular, pathological POSTN with exon 17 is present in both stroma and cancer, but it is unclear whether the stroma or cancer pathological POSTN should be suppressed.

We transplanted 4T1 cells (breast cancer) secreting POSTN with exon 17 into 17KO mice lacking POSTN exon 17 to suppress stromal POSTN with exon 17. The results show that 17KO mice had smaller primary tumors and fewer metastases. Furthermore, to suppress cancer POSTN with exon 17, 4T1 cells transfected with POSTN exon 17 skipping oligo or control oligo were transplanted from the tail vein into the lungs. The results show that POSTN exon 17 skipping oligo significantly suppressed lung metastasis.

These findings suggest that it is important to suppress POSTN exon 17 in both stroma and cancer. Antibody targeting POSTN exon 17 may be a therapeutic candidate for breast cancer.

The extracellular matrix (ECM) is an abundant noncellular component of most solid tumors known to support tumor progression and metastasis. The interplay between the ECM and cancer therapeutics opens up new avenues in understanding cancer biology. While the ECM is known to protect the tumor from anticancer agents by serving as a biomechanical barrier, emerging studies show that various cancer therapies induce ECM remodeling, resulting in therapy resistance and tumor progression. This review discusses critical issues in this field including how the ECM influences treatment outcome, how cancer therapies affect ECM remodeling, and the challenges associated with targeting the ECM. Significance: The intricate relationship between the extracellular matrix (ECM) and cancer therapeutics reveals novel insights into tumor biology and its effective treatment. While the ECM may protect tumors from anti-cancer agents, recent research highlights the paradoxical role of therapy-induced ECM remodeling in promoting treatment resistance and tumor progression. This review explores the key aspects of the interplay between ECM and cancer therapeutics.

Breast cancer is the most common malignancy accounting for 12.5% of all newly diagnosed cancer cases across the globe. Breast cancer cells are known to metastasize to distant organs (i.e., brain), wherein they can exhibit a dormant phenotype for extended time periods. These dormant cancer cells exhibit reduced proliferation and therapeutic resistance. However, the mechanisms by which dormant cancer cells exhibit resistance to therapy, in the context of brain metastatic breast cancer (BMBC), is not well understood. Herein, we utilized hyaluronic acid (HA) hydrogels with varying stiffnesses to study drug responsiveness in dormant vs. proliferative BMBC cells. It was found that cells cultured on soft HA hydrogels (∼0.4 kPa) that showed a non-proliferative (dormant) phenotype exhibited resistance to Paclitaxel or Lapatinib. In contrast, cells cultured on stiff HA hydrogels (∼4.5 kPa) that showed a proliferative phenotype exhibited responsiveness to Paclitaxel or Lapatinib. Moreover, dormancy-associated resistance was found to be due to upregulation of the serum/glucocorticoid regulated kinase 1 (SGK1) gene which was mediated, in part, by the p38 signaling pathway. Accordingly, SGK1 inhibition resulted in a dormant-to-proliferative switch and response to therapy. Overall, our study demonstrates that matrix stiffness influences dormancy-associated therapy response mediated, in part, via the p38/SGK1 axis.