• Actin cytoskeleton
• Actin polymerization
• Hepatocellular carcinoma
• Protein synthesis
• Tanshinone IIA

• Humans
• Actins
• rho GTP-Binding Proteins/pharmacology
• Cell Proliferation
• Carcinoma, Hepatocellular/drug therapy
• Liver Neoplasms
• Cytoskeleton
• Actin Cytoskeleton
• Cell Line, Tumor
• Apoptosis
• Abietanes

• 2020A1515110329, 2023A1515012549, 2019B1515120004 GuangDong Basic and Applied Basic Research Foundation
• 202102021139 Science and Technology Projects in Guangzhou
• YN2019QL06] Science and Technology Research Project of Traditional Chinese Medicine of Guangdong Provincial Hospital of Chinese Medicine
• SL2024A04J00258 Guangzhou Basic and Applied Basic Research Scheme

• cancer biology
• cellular mechanisms
• computational biology
• computational modelling
• human
• invasive pattern
• mouse
• systems biology
• tumour microenvironment

• Humans
• Adherens Junctions
• Proteolysis
• Neoplasm Invasiveness/pathology
• Cell Line, Tumor
• Carcinoma, Squamous Cell/pathology

• FC001144 Cancer Research UK
• FC001144 Medical Research Council
• FC001144 Wellcome Trust
• FC001003 Cancer Research UK
• FC001003 Wellcome Trust
• FC001003 Medical Research Council
• 28990 Cancer Research UK
• Japan Society for the Promotion of Science
• Marie Curie
• Uehara Memorial Foundation
• Francis Crick Institute
• Kitasato University
• European Research Council

Accumulating evidence indicates that mitotic protein kinases are involved in metastatic migration as well as tumorigenesis. Protein kinases and cytoskeletal proteins play a role in the efficient release of metastatic cells from a tumor mass in the tumor microenvironment, in addition to playing roles in mitosis. Mitotic protein kinases, including Polo-like kinase 1 (PLK1) and Aurora kinases, have been shown to be involved in metastasis in addition to cell proliferation and tumorigenesis, depending on the phosphorylation status and cellular context. Although the genetic programs underlying mitosis and metastasis are different, the same protein kinases and cytoskeletal proteins can participate in both mitosis and cell migration/invasion, resulting in migratory tumors. Cytoskeletal remodeling supports several cellular events, including cell division, movement, and migration. Thus, understanding the contributions of cytoskeletal proteins to the processes of cell division and metastatic motility is crucial for developing efficient therapeutic tools to treat cancer metastases. Here, we identify mitotic kinases that function in cancer metastasis as well as tumorigenesis. Several mitotic kinases, namely, PLK1, Aurora kinases, Rho-associated protein kinase 1, and integrin-linked kinase, are considered in this review, as an understanding of the shared machineries between mitosis and metastasis could be helpful for developing new strategies to treat cancer.

Improving understanding of the mechanisms linking cell division and cancer spread (metastasis) could provide novel strategies for treatment. A group of enzymes involved in cell division (mitosis) are also thought to play critical roles in the spread of cancers. Hyungshin Yim at Hanyang University in Ansan, South Korea, and co-workers in Korea and the USA reviewed the roles of several mitotic enzymes that are connected with metastasis as well as tumorigenesis. They discussed how these enzymes modify cytoskeletal proteins and other substrates during cancer progression. Some regulatory control of cell cytoskeletal structures is required for cancer cells to metastasize. Recent research has uncovered crosstalk between mitotic enzymes and metastatic cytoskeletal molecules in various cancers. Targeting mitotic enzymes and the ways they influence cytoskeletal mechanisms could provide valuable therapeutic strategies for suppressing metastasis.

• ROCK inhibition
• enhanced antigen presentation
• injectable thermogel
• tumor radiofrequency ablation

• Animals
• Hydrogels
• Immunity
• Immunotherapy
• Mice
• Neoplasms
• Radiofrequency Ablation

• Rho GTPases
• cancer
• clinical opportunities
• signalling

• Angiogenesis
• Astrocyte
• Ischemic stroke
• Neurogenesis
• Shh

• Animals
• Astrocytes/metabolism
• Brain Ischemia/metabolism
• Humans
• Neurogenesis/physiology
• Neurons/metabolism
• rho-Associated Kinases/metabolism
• rhoA GTP-Binding Protein/metabolism

The invasive tumor front (the tumor–host interface) is vitally important in malignant cell progression and metastasis. Tumor cell interactions with resident and infiltrating host cells and with the surrounding extracellular matrix and secreted factors ultimately determine the fate of the tumor. Herein we focus on the invasive tumor front, making an in-depth characterization of reticular fiber scaffolding, infiltrating immune cells, gene expression, and epigenetic profiles of classified aggressive primary uterine adenocarcinomas (24 patients) and leiomyosarcomas (11 patients). Sections of formalin-fixed samples before and after microdissection were scanned and studied. Reticular fiber architecture and immune cell infiltration were analyzed by automatized algorithms in colocalized regions of interest. Despite morphometric resemblance between reticular fibers and high presence of macrophages, we found some variance in other immune cell populations and distinctive gene expression and cell adhesion-related methylation signatures. Although no evident overall differences in immune response were detected at the gene expression and methylation level, impaired antimicrobial humoral response might be involved in uterine leiomyosarcoma spread. Similarities found at the invasive tumor front of uterine adenocarcinomas and leiomyosarcomas could facilitate the use of common biomarkers and therapies. Furthermore, molecular and architectural characterization of the invasive front of uterine malignancies may provide additional prognostic information beyond established prognostic factors.

• epigenetic profiles
• extracellular matrix
• gene expression
• immune cells
• reticular fibers
• tumor microenvironment
• tumor-host interface

• Chemotherapy-induced senescence
• Rho/ROCK pathway
• Senescence-associated secretory phenotype
• Senescent cell secretome
• Senotherapeutic

The attachment of cells to the extracellular matrix (ECM) is the hallmark of structure–function stability and well-being. ECM detachment in localized tumors precedes abnormal dissemination of tumor cells culminating in metastasis. Programmed cell death (PCD) is activated during tumorigenesis to clear off ECM-detached cells through “anoikis.” However, cancer cells develop several mechanisms for abrogating anoikis, thus promoting their invasiveness and metastasis. Specific factors, such as growth proteins, pH, transcriptional signaling pathways, and oxidative stress, have been reported as drivers of anoikis resistance, thus enhancing cancer proliferation and metastasis. Recent studies highlighted the key contributions of metabolic pathways, enabling the cells to bypass anoikis. Therefore, understanding the mechanisms driving anoikis resistance could help to counteract tumor progression and prevent metastasis. This review elucidates the dynamics employed by cancer cells to impede anoikis, thus promoting proliferation, invasion, and metastasis. In addition, the authors have discussed other metabolic intermediates (especially amino acids and nucleotides) that are less explored, which could be crucial for anoikis resistance and metastasis.

• ECM detachment
• anoikis
• anoikis resistance
• metabolism
• tumor metastasis

Rhabdomyosarcoma (RMS) is a predominant soft tissue tumor in children and adolescents. For high-grade RMS with metastatic involvement, the 3-year overall survival rate is only 25 to 30%. Thus, understanding the regulatory mechanisms involved in promoting the metastasis of RMS is important. Here, we demonstrate for the first time that the SNAIL transcription factor regulates the metastatic behavior of RMS both in vitro and in vivo. SNAIL upregulates the protein expression of EZRIN and AKT, known to promote metastatic behavior, by direct interaction with their promoters. Our data suggest that SNAIL promotes RMS cell motility, invasion and chemotaxis towards the prometastatic factors: HGF and SDF-1 by regulating RHO, AKT and GSK3β activity. In addition, miRNA transcriptome analysis revealed that SNAIL-miRNA axis regulates processes associated with actin cytoskeleton reorganization. Our data show a novel role of SNAIL in regulating RMS cell metastasis that may also be important in other mesenchymal tumor types and clearly suggests SNAIL as a promising new target for future RMS therapies.

• AKT kinase
• EZRIN
• SNAIL transcription factor
• microRNA (miRNA)
• rhabdomyosarcoma (RMS)
• tumor metastasis

The treatment of metastatic osteosarcoma (OS) remains a challenge for oncologists, and novel therapeutic strategies are urgently needed. An understanding of the pathways that regulate OS dissemination is required for the design of novel treatment approaches. We recently identified Rho-associated coiled-coil containing protein kinase 2 (ROCK2) as a crucial driver of OS cell migration. In this study, we explored the impact of ROCK2 disruption on the metastatic capabilities of OS cells and analyzed its functional relationship with Yes-associated protein-1 (YAP), the main transcriptional mediator of mechanotransduction signaling.

The effects of ROCK2 depletion on metastasis were studied in NOD Scid gamma (NSG) mice injected with U-2OS cells in which ROCK2 expression had been stably silenced. Functional studies were performed in vitro in human U-2OS cells and in three novel cell lines derived from patient-derived xenografts (PDXs) by using standard methods to evaluate malignancy parameters and signaling transduction. The nuclear immunostaining of YAP and the evaluation of its downstream targets Cysteine Rich Angiogenic Inducer 6, Connective Tissue Growth Factor and Cyclin D1 by quantitative PCR were performed to analyze YAP activity. The effect of the expression and activity of ROCK2 and YAP on tumor progression was analyzed in 175 OS primary tumors.

The silencing of ROCK2 markedly reduced tumor growth and completely abolished the metastatic ability of U-2OS cells. The depletion of ROCK2, either by pharmacological inhibition or silencing, induced a dose- and time-dependent reduction in the nuclear expression and transcriptional activity of YAP. The nuclear expression of YAP was observed in 80/175 (46%) tumor samples and was significantly correlated with worse patient prognosis and a higher likelihood of metastasis and death. The use of verteporfin, a molecule that specifically inhibits the TEAD–YAP association, remarkably impaired the growth and migration of OS cells in vitro. Moreover to inhibiting YAP activity, our findings indicate that verteporfin also affects the ROCK2 protein and its functions.

We describe the functional connection between ROCK2 and YAP in the regulation of OS cell migration and metastasis formation. These data provide support for the use of verteporfin as a possible therapeutic option to prevent OS cell dissemination.

• Metastasis
• Osteosarcoma
• ROCK2
• Verteporfin
• YAP

Hepatic carcinoma with metastasis remains incurable, and clinical diagnostic methods lacked adequate sensitivity and specificity. Therefore, seeking effectively diagnostic biomarkers is still essential for it. RHOC was reported to be linked to metastasis of hepatic carcinoma. However, almost all of the studies used tissues as detection samples, which was not ideal for clinical course minoring. Therefore, here, it was aimed to use PBMC samples that were not only easily accessible but also minimally invasive to determine the expression and biological interaction network of RHOC for hepatic carcinoma with metastasis.

PBMC samples were isolated. Then, RNA-seq was performed to identify the DEGs between hepatic carcinoma with metastasis and hepatic carcinoma with solitary tumor. Subsequently, q-RT-PCR was used to verify the expression level of RHOC. Finally, bioinformatic analysis was used to present the biological interaction network of RHOC for hepatic carcinoma with metastasis in PBMC samples.

The results of both RNA-seq and q-RT-PCR showed that the expression level of RHOC was significantly higher in the PBMC samples of hepatic carcinoma with metastasis than in those of hepatic carcinoma with solitary tumor. By using variety of bioinformatic analysis platforms, in PBMCs, 18 co-expression genes with RHOC were identified and their interaction network showed that MYL9 and RHOC had the highest edge evidence, and were involved in some cell migration-related pathways.

Our results indicated that RHOC in PBMCs could be potentially minimally invasive indicators for the diagnosis and clinical course supervision of hepatic carcinoma with metastasis, and its biological interaction network determined based on bioinformatic methods would lay a foundation for further study of the role of RHOC in tumor invasion and metastasis.

• PBMC
• RHOC
• diagnosis
• hepatic carcinoma
• metastasis

Rho-associated protein kinase 1 (ROCK1), a member of the ROCK family, serves an important function in cell migration and invasion in neoplasms. ROCK1 has been found to be overexpressed in several types of cancers. However, the role of ROCK1 in non-small-cell lung cancer (NSCLC) is poorly understood. In the present study, ROCK1 was found to be overexpressed in NSCLC cells and tissues, and it was associated with poor survival of NSCLC patients. Subsequently, ROCK1 knockdown NSCLC cell lines were established using shRNA. ROCK1 knockdown significantly reduced the migration and invasion ability in the cell monolayer scratching and Transwell assays. ROCK1 knockdown was also found to markedly inhibit cell adhesion ability. Moreover, the phosphorylation of focal adhesion kinase (FAK) was inhibited by ROCK1 knockdown, reducing NSCLC cell migration and invasion ability. This mechanistic study revealed that ROCK1 significantly enhanced cell migration and invasion by inhibiting the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/FAK pathway. More importantly, the interruption of the PTEN/PI3K/FAK pathway markedly rescued the inhibition of cell migration and invasion mediated by ROCK1 knockdown. Taken together, these results suggest a novel role for ROCK1 in cell migration and invasion by inhibiting cell adhesion ability, and indicate that ROCK1 may be of value as a therapeutic target for the treatment of NSCLC.

• biomarkers
• biomechanics
• lung
• metastases
• metastatic niche

• P_20180064630 and Ricerca Corrente 2018 to GMS and 2019 to SB

• GTPases
• collective migration
• colorectal carcinoma
• invasion
• leader cells

• Adenocarcinoma/genetics
• Adenocarcinoma/metabolism
• Animals
• Caco-2 Cells
• Cell Culture Techniques/methods
• Cell Line, Tumor
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Gene Expression Regulation, Neoplastic
• Guanine Nucleotide Exchange Factors/metabolism
• Humans
• Mice
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Organoids/cytology
• Organoids/metabolism
• RNA, Small Interfering/pharmacology
• rho-Associated Kinases/genetics
• rho-Associated Kinases/metabolism

• Subvention comité IDF 2019 LNCC comité IDF
• FDT20160435539 Fondation pour la recherche medicale
• P30 CA008748 NCI NIH HHS
• French government MESR PhD fellowship
• 2018-1-PLBIO-04-IGR-1 INCA PLBIO
• Gustave Roussy Foundation
• CNRS/INSERM ATIP-AVENIR Programme

• Adult
• Aged
• Apoptosis
• Cell Movement
• Cell Proliferation
• Chromosome Deletion
• Chromosomes, Human, Pair 8/genetics
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Humans
• Male
• MicroRNAs/genetics
• Middle Aged
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/pathology
• Tumor Cells, Cultured

• U01 CA184966 NCI NIH HHS
• National Institutes of Health
• National Cancer Institute
• Department of Defense Prostate Cancer Research Program
• Prostate Cancer Biorepository Network

The extracellular matrix (ECM) is known to play an important role in the health of cells and tissues. Not only are chemical signals transmitted via bonds and tightly controlled diffusion, but the structure of the ECM also provides important physical signaling for the cells attached to it. The structure is composed of a mesh of fibrous proteins, such as collagen, embedded in a hydrated gel matrix of glycosaminoglycans. To study cell behavior with respect to the combined morphology and mechanics of such matrices is not currently possible with the types of 3D cell culture matrices available. Most of the cell culture matrices are single-phase bio- or polymeric hydrogels. Therefore, here we developed a continuous hybrid manufacturing process to make fiber-reinforced composite hydrogels. A far field electrospinning process was used to deposit the fibrous component with the aid of guiding electrodes; and a gravity-assisted, droplet-based system controlled the rate of addition of the cell-laden hydrogel component. The addition of the fibrous component slightly increased the elastic modulus of the pure hydrogel. The cells that were embedded into the fiber-reinforced hydrogels were viable for 8 days. The cells were randomly placed in the matrix such that some had no contact to the fibers and others were initially in proximity to fibers. The cells with no contact to fibers grew into spheroidal clusters within the hydrogel, and those in proximity to the fibers spread out and grew along the fibers showing that the fiber-reinforced hydrogels are able to control cell behavior with morphological cues.

• cell-ECM interaction
• electrospinning
• extracellular matrix
• hydrogel
• mechanobiology

• Rho-associated protein kinase
• actin polymerization
• cytoskeleton
• smooth muscle contraction

• Angiogenesis
• Cornea
• Eye
• Inflammation
• Limbal stem cell deficiency
• Neovascularization
• Vascularization

• RhoA/ROCK signaling
• cancer cell scattering and invasion
• carcinoma-associated fibroblasts
• insulin-like growth factor-1
• plasminogen activator inhibitor-1

• Gastric cancer
• MYH9
• Metastasis
• MicroRNA-647
• SRF.

• Anilides/pharmacology
• Anilides/therapeutic use
• Antagomirs/pharmacology
• Antagomirs/therapeutic use
• Base Sequence
• Benzamides/pharmacology
• Benzamides/therapeutic use
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Movement/genetics
• Cell Proliferation/drug effects
• Down-Regulation/drug effects
• Down-Regulation/genetics
• Female
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Male
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Middle Aged
• Molecular Motor Proteins/genetics
• Molecular Motor Proteins/metabolism
• Multivariate Analysis
• Myosin Heavy Chains/genetics
• Myosin Heavy Chains/metabolism
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Prognosis
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Serum Response Factor/genetics
• Serum Response Factor/metabolism
• Signal Transduction/drug effects
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Survival Analysis
• rho GTP-Binding Proteins/metabolism

Frizzled receptors are the mediators of the wnt canonical and non-canonical pathways, which play fundamental roles in cell differentiation and organism development. A large body of work indicates that dysregulation of wnt signalling is a feature of oncogenic transformation, but most of the studies published so far focus on the assessment of the consequences of aberrations of the canonical pathway in human cancer. In this review, we discuss the emerging role of the wnt non-canonical pathway regulated by frizzled receptor 6 (Fzd6) in the pathogenesis of different types of human malignancies. The function played by Fzd6 in the physiology of normal and cancer cells has been highlighted in the view that an increased knowledge of the signalling pathways upstream and downstream of this receptor could ultimately result in the identification of new targets for cancer therapy.

• ROCK kinases
• collagen remodeling
• extracellular matrix
• pancreatic cancer
• tumor cell invasion

• Adenocarcinoma/pathology
• Animals
• Carcinoma, Pancreatic Ductal/pathology
• Collagen/metabolism
• Gene Expression Profiling
• Gene Regulatory Networks
• Humans
• Mice
• Signal Transduction
• Survival Analysis
• rho-Associated Kinases/metabolism

• 12946 Cancer Research UK
• A18276 Cancer Research UK
• 15565 Cancer Research UK
• 18276 Cancer Research UK
• 20409 Cancer Research UK
• 11650 Cancer Research UK

Lung cancer is the most lethal cancer type worldwide, with the majority of patients presenting with advanced stage disease. Targeting early stage disease pathogenesis would allow dramatic improvements in lung cancer patient survival. Recently, cell migration has been shown to be an integral process in early lung cancer ontogeny, with preinvasive lung cancer cells shown to migrate across normal epithelium prior to developing into invasive disease. TP53 mutations are the most abundant mutations in human nonsmall cell lung cancers and have been shown to increase cell migration via regulation of Rho-GTPase protein activity. In this review, we explore the possibility of targeting TP53-mediated Rho-GTPase activity in early lung cancer and the opportunities for translating this preclinical research into effective therapies for early stage lung cancer patients.

Preinvasive lung cancer cell migration is a potential novel therapeutic target in early lung cancerhttp://ow.ly/FJGm305JxMQ

• Breast cancer
• HOTAIR
• MRTF-A
• Rho-signaling
• Transcription

• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• Cell Line, Tumor
• Cell Nucleus/metabolism
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Models, Biological
• Promoter Regions, Genetic
• Protein Binding/genetics
• RNA Polymerase II/metabolism
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Serum Response Factor/metabolism
• Signal Transduction
• Trans-Activators/metabolism
• Transcription, Genetic
• rho-Associated Kinases/metabolism
• rhoC GTP-Binding Protein/metabolism

• Connective tissue growth factor
• Suture
• Tensile force
• Vascular endothelial growth factor
• Vascularization

• Adolescent
• Animals
• Connective Tissue Growth Factor/metabolism
• Cranial Sutures/blood supply
• Cranial Sutures/metabolism
• Gene Expression Regulation/physiology
• Humans
• Infant
• MAP Kinase Signaling System/physiology
• Male
• Mice
• Mice, Inbred ICR
• Neovascularization, Physiologic/physiology
• Stress, Mechanical
• Tensile Strength/physiology
• Vascular Endothelial Growth Factor A/biosynthesis
• rho-Associated Kinases/metabolism

• Hprt locus
• ROCK
• actomyosin contractility

• Animals
• Cytochrome P-450 CYP1A1/genetics
• Epidermis/metabolism
• Estrogen Receptor alpha/biosynthesis
• Estrogen Receptor alpha/genetics
• Female
• Gene Expression Regulation, Developmental/drug effects
• Humans
• Integrases/genetics
• Intestinal Mucosa/metabolism
• Mammary Glands, Animal/metabolism
• Mice
• Organ Specificity/genetics
• Promoter Regions, Genetic/genetics
• Recombinant Fusion Proteins/biosynthesis
• Recombinant Fusion Proteins/genetics
• Signal Transduction/drug effects
• Tamoxifen/administration & dosage
• rho-Associated Kinases/biosynthesis
• rho-Associated Kinases/genetics

• 18276 Cancer Research UK
• A18276 Cancer Research UK

Chronic infection with cagA-positive Helicobacter pylori is the strongest risk factor for atrophic gastritis, peptic ulcers, and gastric cancer. CagA, the product of the cagA gene, is a bacterial oncoprotein, which, upon delivery into gastric epithelial cells, binds to and inhibits the polarity-regulating kinase, partitioning-defective 1b (PAR1b) [also known as microtubule affinity-regulating kinase 2 (MARK2)], via its CagA multimerization (CM) motif. The inhibition of PAR1b elicits junctional and polarity defects, rendering cells susceptible to oncogenesis. Notably, the polymorphism in the CM motif has been identified among geographic variants of CagA, differing in either the copy number or the sequence composition. In this study, through quantitative analysis of the complex formation between CagA and PAR1b, we found that several CagA species have acquired elevated PAR1b-binding activity via duplication of the CM motifs, while others have lost their PAR1b-binding activity. We also found that strength of CagA-PAR1b interaction was proportional to the degrees of stress fiber formation and tight junctional disruption by CagA in gastric epithelial cells. These results indicate that the CM polymorphism is a determinant for the magnitude of CagA-mediated deregulation of the cytoskeletal system and thereby possibly affects disease outcome of cagA-positive H. pylori infection, including gastric cancer.

Tumor angiogenesis promotes tumor growth and metastasis. Here, we use automated sequential microprinting of tumor and endothelial cells in extracellular matrix (ECM) scaffolds to study its mechanical aspects. Quantitative reflection microscopy shows that tumor spheroids induce radial orientation of the surrounding collagen fiber network up to a distance of five times their radius. Across a panel of ~20 different human tumor cell lines, remote collagen orientation is correlated with local tumor cell migration behavior. Tumor induced collagen orientation requires contractility but is remarkably resistant to depletion of collagen-binding integrins. Microvascular endothelial cells undergo directional migration towards tumor spheroids once they are within the tumor-oriented collagen fiber network. Laser ablation experiments indicate that an intact physical connection of the oriented network with the tumor spheroid is required for mechanical sensing by the endothelial cells. Together our findings indicate that, in conjunction with described activities of soluble angiogenic factors, remote physical manipulation of the ECM network by the tumor can help to steer angiogenesis.

• Antineoplastic Agents/therapeutic use
• Drug Repositioning
• Gamma Rays/therapeutic use
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/therapy
• Neovascularization, Pathologic/genetics
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/pathology
• Neovascularization, Pathologic/therapy
• Protein Kinase Inhibitors/therapeutic use
• Radiation-Sensitizing Agents/therapeutic use
• Signal Transduction
• Tumor Microenvironment
• Vasodilator Agents/therapeutic use
• rho-Associated Kinases/antagonists & inhibitors
• rho-Associated Kinases/genetics

• 103721 Wellcome Trust
• 17263 Cancer Research UK

Numerous large scale genomics studies have demonstrated that cancer is a molecularly heterogeneous disease, characterized by acquired changes in the structure and DNA sequence of tumor genomes. More recently, the role of the equally complex tumor microenvironment in driving the aggressiveness of this disease is increasingly being realized. Tumor cells are surrounded by activated stroma, creating a dynamic environment that promotes cancer development, metastasis and chemoresistance. The Rho family of small GTPases plays an essential role in the regulation of cell shape, cytokinesis, cell adhesion, and cell motility. Importantly, these processes need to be considered in the context of a complex 3-dimensional (3D) environment, with reciprocal feedback and cross-talk taking place between the tumor cells and host environment. Here we discuss the role of molecular networks involving Rho GTPases in cancer, and the therapeutic implications of inhibiting Rho signaling in both cancer cells and the emerging concept of targeting the surrounding stroma.

• ECM
• FLIM
• FRET
• Rho GTPase
• Rho inhibitors
• cancer stroma
• chemoresistance
• collagen
• intravital imaging

• Endothelial cells
• ROCKs
• Rho GTPases
• RhoC
• cancer metastasis
• cell migration

• Cell Communication
• Cell Line, Tumor
• Human Umbilical Vein Endothelial Cells/metabolism
• Human Umbilical Vein Endothelial Cells/pathology
• Humans
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• rho GTP-Binding Proteins/genetics
• rho GTP-Binding Proteins/metabolism
• rho-Associated Kinases/genetics
• rho-Associated Kinases/metabolism
• rhoC GTP-Binding Protein

• 11-0674 Worldwide Cancer Research
• 15961 Cancer Research UK
• 20407 Cancer Research UK
• BB/E004083/2 Biotechnology and Biological Sciences Research Council

• adaptation to extracellular matrix
• cancer cell motility
• cell–extracellular matrix adhesion feedback
• plasma membrane blebbing
• plasticity of motility

• Adaptation, Physiological/physiology
• Adaptation, Physiological/radiation effects
• Algorithms
• Animals
• Cell Adhesion/physiology
• Cell Movement/physiology
• Cell Plasticity/physiology
• Computer Simulation
• Ecosystem
• Extracellular Matrix/physiology
• Humans
• Mechanotransduction, Cellular/physiology
• Models, Biological

• 10748 Cancer Research UK
• 15154 Cancer Research UK
• MR/L009056/1 Medical Research Council

• MEK
• NRAS
• ROCK
• melanoma
• targeted therapy

• Cancer
• ECM stiffness
• Free radicals
• Mechanosignaling
• Tumor metabolism
• Tumor microenvironment

• Disease Progression
• Extracellular Matrix/metabolism
• Humans
• Neoplasms/metabolism
• Neoplasms/pathology
• Tumor Microenvironment

• R01 CA114462 NCI NIH HHS
• R01 CA169175 NCI NIH HHS
• U01ES019458 NIEHS NIH HHS
• R01CA158668 NCI NIH HHS
• U54CA143836 NCI NIH HHS
• R01 CA170851 NCI NIH HHS
• R01 CA136590 NCI NIH HHS
• R01 CA158668 NCI NIH HHS
• R01 CA138818 NCI NIH HHS
• F32 CA174319 NCI NIH HHS
• R33CA183685-01 NCI NIH HHS
• R01CA170851 NCI NIH HHS
• T32 HL007544 NHLBI NIH HHS
• CA138818-01A1 NCI NIH HHS
• T32HL007544 NHLBI NIH HHS
• R01 CA155664 NCI NIH HHS
• F32CA174319 NCI NIH HHS
• R01CA114462 NCI NIH HHS
• R01 CA174929 NCI NIH HHS
• R01CA142833 NCI NIH HHS
• U54 CA163155 NCI NIH HHS
• U01 ES019458 NIEHS NIH HHS
• R01 CA192914 NCI NIH HHS
• U54CA163155-01 NCI NIH HHS
• R33 CA183685 NCI NIH HHS
• R21EB008811 NIBIB NIH HHS
• R21 EB008811 NIBIB NIH HHS
• R01 CA142833 NCI NIH HHS
• U54 CA143836 NCI NIH HHS