Rho, ROCK and actomyosin contractility in metastasis as drug targets

Metastasis is the spread of cancer cells around the body and the cause of the majority of cancer deaths. Metastasis is a very complex process in which cancer cells need to dramatically modify their cytoskeleton and cope with different environments to successfully colonize a secondary organ. In this review, we discuss recent findings pointing at Rho-ROCK or actomyosin force (or both) as major drivers of many of the steps required for metastatic success. We propose that these are important drug targets that need to be considered in the clinic to palliate metastatic disease.

• Publication year

  2016

• Venue

  F1000Research

• Publication date

  2016-04-29

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.12688/f1000research.7909.1PMID 27158478PMCID 4856114
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Confinement and low adhesion induce fast amoeboid migration of slow mesenchymal cells.

  2015cited by this paper
• Mutant B-Raf(V600E) Promotes Melanoma Paracellular Transmigration by Inducing Thrombin-mediated Endothelial Junction Breakdown*

  2015cited by this paper
• TGF-β-Induced Transcription Sustains Amoeboid Melanoma Migration and Dissemination

  2015cited by this paper
• Translational value of mouse models in oncology drug development

  2015cited by this paper
• RhoC and ROCKs regulate cancer cell interactions with endothelial cells

  2015cited by this paper
• Real-Time Imaging Reveals Local, Transient Vascular Permeability, and Tumor Cell Intravasation Stimulated by TIE2hi Macrophage-Derived VEGFA.

  2015cited by this paper
• Reactivation of p53 by a Cytoskeletal Sensor to Control the Balance Between DNA Damage and Tumor Dissemination

  2015cited by this paper
• Rho kinase inhibitors block melanoma cell migration and inhibit metastasis.

  2015cited by this paper
• Cortical Contractility Triggers a Stochastic Switch to Fast Amoeboid Cell Motility

  2015cited by this paper
• Rho GTPase signalling in cell migration

  2015cited by this paper
• Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization

  2015cited by this paper
• Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts

  2015cited by this paper
• Tissue invasion and metastasis: Molecular, biological and clinical perspectives.

  2015cited by this paper
• Metastasis review: from bench to bedside

  2014cited by this paper
• Rho GTPases modulate malignant transformation of tumor cells

  2014cited by this paper
• Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway.

  2014cited by this paper
• Diverse matrix metalloproteinase functions regulate cancer amoeboid migration

  2014cited by this paper
• Rho-directed forces in collective migration

  2014cited by this paper
• Contribution of p53 to metastasis.

  2014cited by this paper
• LIF mediates proinvasive activation of stromal fibroblasts in cancer.

  2014cited by this paper
• Beyond TGFβ: roles of other TGFβ superfamily members in cancer

  2013cited by this paper
• Epithelial–mesenchymal plasticity in carcinoma metastasis

  2013cited by this paper
• Noninvasive Molecular Imaging Using Reporter Genes

  2013cited by this paper
• Mechano-transduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer associated fibroblasts

  2013cited by this paper
• Innate and adaptive immune cells in the tumor microenvironment

  2013cited by this paper
• Microenvironmental regulation of tumor progression and metastasis

  2013cited by this paper
• Identification of novel ROCK inhibitors with anti-migratory and anti-invasive activities

  2013cited by this paper
• Dimensions in cell migration.

  2013cited by this paper
• Crossing the endothelial barrier during metastasis

  2013cited by this paper
• Macrophage contact induces RhoA GTPase signaling to trigger tumor cell intravasation

  2013cited by this paper
• Intravital multiphoton imaging reveals multicellular streaming as a crucial component of in vivo cell migration in human breast tumors

  2013cited by this paper
• Origins of metastatic traits.

  2013cited by this paper
• Matrix geometry determines optimal cancer cell migration strategy and modulates response to interventions

  2013cited by this paper
• FilGAP, a Rho/Rho-associated protein kinase–regulated GTPase-activating protein for Rac, controls tumor cell migration

  2012cited by this paper
• Cdc42 promotes transendothelial migration of cancer cells through β1 integrin

  2012cited by this paper
• Fibroblast growth factors preserve blood-brain barrier integrity through RhoA inhibition after intracerebral hemorrhage in mice.

  2012cited by this paper
• WNT signalling pathways as therapeutic targets in cancer

  2012cited by this paper
• Rho‐associated kinases in tumorigenesis: re‐considering ROCK inhibition for cancer therapy

  2012cited by this paper
• Nanog and Oct4 overexpression increases motility and transmigration of melanoma cells

  2012cited by this paper
• Inhibition of Rho kinase by hydroxyfasudil attenuates brain edema after subarachnoid hemorrhage in rats.

  2012cited by this paper
• The Role of Dlc1 Isoform 2 in K-Ras2G12D Induced Thymic Cancer

  2012cited by this paper
• Rho GTPases and cancer cell transendothelial migration.

  2012cited by this paper
• Hallmarks of cancer: the next generation.

  2011cited by this paper
• RasGRF suppresses Cdc42-mediated tumour cell movement, cytoskeletal dynamics and transformation

  2011cited by this paper
• Mechanical signaling through the cytoskeleton regulates cell proliferation by coordinated focal adhesion and Rho GTPase signaling

  2011cited by this paper
• Pigment epithelium-derived factor blocks tumor extravasation by suppressing amoeboid morphology and mesenchymal proteolysis.

  2011cited by this paper
• Oncogenic BRAF induces melanoma cell invasion by downregulating the cGMP-specific phosphodiesterase PDE5A.

  2011cited by this paper
• An ezrin-rich, rigid uropod-like structure directs movement of amoeboid blebbing cells

  2011cited by this paper
• Noninvasive cell-tracking methods

  2011cited by this paper
• Cancer invasion and the microenvironment: plasticity and reciprocity.

  2011cited by this paper
• A Synthetic Biology Approach Reveals a CXCR4-G13-Rho Signaling Axis Driving Transendothelial Migration of Metastatic Breast Cancer Cells

  2011cited by this paper
• ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma.

  2011cited by this paper
• Tumor metastasis: molecular insights and evolving paradigms.

  2011cited by this paper
• AACR centennial series: the biology of cancer metastasis: historical perspective.

  2010cited by this paper
• Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain.

  2010cited by this paper
• Coordinated RhoA signaling at the leading edge and uropod is required for T cell transendothelial migration

  2010cited by this paper
• Myosin light chain kinase mediates transcellular intravasation of breast cancer cells through the underlying endothelial cells: a three-dimensional FRET study

  2010cited by this paper
• The plasticity of cytoskeletal dynamics underlying neoplastic cell migration.

  2010cited by this paper
• Roles of TGFβ in metastasis

  2009cited by this paper
• The metastatic niche: adapting the foreign soil

  2009cited by this paper
• Mechanical modes of 'amoeboid' cell migration.

  2009cited by this paper
• Myocardin-Related Transcription Factors and SRF are required for cytoskeletal dynamics, invasion and experimental metastasis

  2009cited by this paper
• ‘Loss of pigment epithelium-derived factor enables migration, invasion and metastatic spread of human melanoma’

  2009cited by this paper
• Epithelial-mesenchymal transitions in development and disease.

  2009cited by this paper
• Inhibition of rho-associated kinase signaling prevents breast cancer metastasis to human bone.

  2009cited by this paper
• EphA2 reexpression prompts invasion of melanoma cells shifting from mesenchymal to amoeboid-like motility style.

  2009cited by this paper
• Localised and reversible TGFβ signalling switches breast cancer cells from cohesive to single cell motility

  2009cited by this paper
• Protein Kinase C-related Kinase and ROCK Are Required for Thrombin-induced Endothelial Cell Permeability Downstream from Galpha12/13 and Galpha11/q

  2008cited by this paper
• DOCK10-mediated Cdc42 activation is necessary for amoeboid invasion of melanoma cells.

  2008cited by this paper
• Protein Kinase C-related Kinase and ROCK Are Required for Thrombin-induced Endothelial Cell Permeability Downstream from Gα12/13 and Gα11/q*

  2008cited by this paper
• Rac activation and inactivation control plasticity of tumor cell movement.

  2008cited by this paper
• Mechanisms by which E-selectin regulates diapedesis of colon cancer cells under flow conditions.

  2008cited by this paper
• Imaging amoeboid cancer cell motility in vivo

  2008cited by this paper
• PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE

  2008cited by this paper
• TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4.

  2008cited by this paper
• Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion

  2007cited by this paper
• Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility

  2007cited by this paper
• Illuminating the metastatic process

  2007cited by this paper
• Genetic determinants of cancer metastasis

  2007cited by this paper
• Co-operative Cdc42 and Rho signalling mediates ephrinB-triggered endothelial cell retraction.

  2007cited by this paper
• Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells

  2007cited by this paper
• Mobility and invasiveness of metastatic esophageal cancer are potentiated by shear stress in a ROCK- and Ras-dependent manner.

  2006cited by this paper
• Involvement of Rho/ROCK signalling in small cell lung cancer migration through human brain microvascular endothelial cells

  2006cited by this paper
• Thrombin induces tumor growth, metastasis, and angiogenesis: Evidence for a thrombin-regulated dormant tumor phenotype.

  2006cited by this paper
• ROCK- and myosin-dependent matrix deformation enables protease-independent tumor-cell invasion in vivo.

  2006cited by this paper
• Reassembly of contractile actin cortex in cell blebs

  2006cited by this paper
• Cancer metastasis: building a framework.

  2006cited by this paper
• Rho GTPases: biochemistry and biology.

  2005cited by this paper
• Cdc42–MRCK and Rho–ROCK signalling cooperate in myosin phosphorylation and cell invasion

  2005cited by this paper
• RhoA activation promotes transendothelial migration of monocytes via ROCK

  2004cited by this paper
• Mini‐review: Transendothelial migration of leukocytes: through the front door or around the side of the house?

  2004cited by this paper
• Inhibition of Xenografted Human Melanoma Growth and Prevention of Metastasis Development by Dual Antiangiogenic/Antitumor Activities of Pigment Epithelium-Derived Factor

  2004cited by this paper
• Myosin phosphatase: Structure, regulation and function

  2004cited by this paper
• ROCKs: multifunctional kinases in cell behaviour

  2003cited by this paper
• Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis

  2003cited by this paper
• RHO–GTPases and cancer

  2002cited by this paper
• The Journal of Cell Biology

  2002cited by this paper
• Epithelial–mesenchymal transitions in tumour progression

  2002cited by this paper
• RhoA is required for monocyte tail retraction during transendothelial migration

  2001cited by this paper
• Activation of RhoA by Thrombin in Endothelial Hyperpermeability: Role of Rho Kinase and Protein Tyrosine Kinases

  2000cited by this paper

• Roles of cytoskeleton in metastasis: from its mechanism to therapeutic strategies

  2026cites this paper
• Keratin as a Potential Prognostic Biomarker for Breast Cancer Progression: An Evidence-Synthesizing Narrative Review

  2026cites this paper
• Orchestrating movement: the role of Caveolin-1 in migration and metastasis

  2025cites this paper
• Cytoplasmic anillin and Ect2 promote RhoA/myosin II-dependent confined migration and invasion

  2025cites this paper
• Decoding force-transmission linkages for therapeutic targeting and engineering

  2025cites this paper
• Anti-metastatic potential of flavonoids for the treatment of cancers: focus on epithelial-mesenchymal transition (EMT) process

  2025cites this paper
• Discovery of ROCK2 inhibitors through computational screening of ZINC database: Integrating pharmacophore modeling, molecular docking, and MD simulations

  2025cites this paper
• Noninvasive Screening of Basal Cell Carcinomas: A Comparison of the Structure and Physical Properties of Large and Small Nodular Lesions Using Vibrational OCT and Histopathology

  2025cites this paper
• Pan-cancer drivers of metastasis

  2025cites this paper
• The Role of Connections Between Cellular and Tissue Mechanical Elements and the Importance of Applied Energy in Mechanotransduction in Cancerous Tissue

  2025cites this paper
• The potential of cytochalasins and other cytochalasans as drugs targeting cancer cell invasiveness and metastasis.

  2025cites this paper
• The Role of Rho Kinase Inhibitors in Corneal Diseases

  2024cites this paper
• Challenges of Regulated Cell Death: Implications for Therapy Resistance in Cancer

  2024cites this paper
• PAK6 acts downstream of IQGAP3 to promote contractility in triple negative breast cancer cells.

  2024cites this paper
• Reduced cell-substrate adhesion formation promotes cell migration in Dictyostelium

  2024cites this paper
• Cytoplasmic accumulation and plasma membrane association of anillin and Ect2 promote confined migration and invasion

  2024cites this paper
• The lysophosphatidic acid-regulated signal transduction network in ovarian cancer cells and its role in actomyosin dynamics, cell migration and entosis

  2023cites this paper
• The Journey of Cancer Cells to the Brain: Challenges and Opportunities

  2023cites this paper
• CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells

  2023cites this paper
• Faulty Metabolism: A Potential Instigator of an Aggressive Phenotype in Cdk5-dependent Medullary Thyroid Carcinoma

  2023cites this paper
• Zinc Finger Proteins in the War on Gastric Cancer: Molecular Mechanism and Clinical Potential

  2023cites this paper
• Retinoic acid receptor β modulates mechanosensing and invasion in pancreatic cancer cells via myosin light chain 2

  2023cites this paper
• Mechanobiology of cancer cell responsiveness to chemotherapy and immunotherapy: mechanistic insights and biomaterial platforms.

  2023cites this paper
• Knockdown of RhoA expression reverts enzalutamide resistance via the p38 MAPK pathway in castration‑resistant prostate cancer.

  2022cites this paper
• Early functional mismatch between breast cancer cells and their tumour microenvironment suppresses long term growth.

  2022cites this paper
• Extracellular matrix profiles determine risk and prognosis of the squamous cell carcinoma subtype of non-small cell lung carcinoma

  2022cites this paper
• How does plasticity of migration help tumor cells to avoid treatment: Cytoskeletal regulators and potential markers

  2022cites this paper
• The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis

  2022cites this paper
• Retinoid acid receptor β mechanically regulates the activity of pancreatic cancer cells

  2022cites this paper
• Tripartite split-GFP assay to identify selective intracellular nanobody that suppresses GTPase RHOA subfamily downstream signaling

  2022cites this paper
• Activity of ROCKII not ROCKI promotes pulmonary metastasis of melanoma cells via modulating Smad2/3-MMP9 and FAK-Src- VEGF signalling.

  2022cites this paper
• The mechanosensor Filamin A/Cheerio promotes tumourigenesis via specific interactions with components of the cell cortex

  2022cites this paper
• Deciphering molecular mechanisms of metastasis: novel insights into targets and therapeutics

  2021cites this paper
• Profiling the expression of pro-metastatic genes in association with the clinicopathological features of primary breast cancer

  2021cites this paper
• Analyzing the Roles of Rho GTPases in Cancer Cell Adhesion to Endothelial Cells Under Flow Conditions.

  2021cites this paper
• Contributions of the Distinct Biophysical Phenotype of Polyploidal Giant Cancer Cells to Cancer Progression.

  2021cites this paper
• Early functional mismatch between breast cancer cells and their tumour microenvironment suppresses long term growth

  2021cites this paper
• Location, location, location: Melanoma cells “living at the edge”

  2021cites this paper
• Role of hypoxia in inhibiting dendritic cells by VEGF signaling in tumor microenvironments: mechanism and application.

  2021cites this paper
• Heterogeneous Pancreatic Stellate Cells Are Powerful Contributors to the Malignant Progression of Pancreatic Cancer

  2021cites this paper
• Early mismatch between cancer cells and their tumour 1 microenvironment blocks long term growth 2 3

  2021cites this paper
• Targeting ROCK activity to disrupt and prime pancreatic cancer for chemotherapy

  2020cites this paper
• Roles of Rho‑associated kinase in lung cancer (Review).

  2020cites this paper
• 3D scaffold materials for skin cancer modeling

  2020cites this paper
• WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion

  2020cites this paper
• Myosins: Driving us towards novel targets and biomarkers in cancer.

  2020cites this paper
• Role of Collagen Fiber Morphology on Ovarian Cancer Cell Migration Using Image-Based Models of the Extracellular Matrix

  2020cites this paper
• Migrastatics – Anti-metastatic Drugs Targeting Cancer Cell Invasion

  2020cites this paper
• Targeting Rho GTPase Signaling Networks in Cancer

  2020cites this paper
• GPER Activation Inhibits Cancer Cell Mechanotransduction and Basement Membrane Invasion via RhoA

  2020cites this paper
• Metastasis: crosstalk between tissue mechanics and tumour cell plasticity

  2020cites this paper
• 6-Substituted purines as ROCK inhibitors with anti-metastatic activity.

  2019cites this paper
• Differential Contributions of Actin and Myosin to the Physical Phenotypes and Invasion of Pancreatic Cancer Cells

  2019cites this paper
• Biophysical properties of intermediate states of EMT outperform both epithelial and mesenchymal states

  2019cites this paper
• Regional Activation of Myosin II in Cancer Cells Drives Tumor Progression via a Secretory Cross-Talk with the Immune Microenvironment

  2019cites this paper
• Unravelling tumour heterogeneity by single-cell profiling of circulating tumour cells

  2019cites this paper
• Rebalancing of actomyosin contractility enables mammary tumor formation upon loss of E-cadherin

  2019cites this paper
• Transition from mesenchymal to bleb‐based motility is predominantly exhibited by CD133‐positive subpopulation of fibrosarcoma cells

  2019cites this paper
• Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

  2019cites this paper
• Substrate stiffness regulated migration and invasion ability of adenoid cystic carcinoma cells via RhoA/ROCK pathway

  2018cites this paper
• Uncovering the signaling landscape controlling breast cancer cell migration identifies splicing factor PRPF4B as a metastasis driver

  2018cites this paper
• Targeting epithelial-to-mesenchymal transition (EMT) in feline oral squamous cell carcinoma (FOSCC)

  2018cites this paper
• Active wetting of epithelial tissues

  2018cites this paper
• Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor

  2018cites this paper
• Quantitative phase imaging unravels new insight into dynamics of mesenchymal and amoeboid cancer cell invasion

  2018cites this paper
• Myosin‐IIA heavy chain phosphorylation on S1943 regulates tumor metastasis

  2018cites this paper
• DDR1 and DDR2 in skin

  2018cites this paper
• Rapid valproic acid-induced modulation of the traumatic proteome in a porcine model of traumatic brain injury and hemorrhagic shock.

  2018cites this paper
• Septins in Cancer and Metastasis

  2018cites this paper
• Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis

  2017cites this paper
• EMT: Mechanisms and therapeutic implications

  2017cites this paper
• Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

  2017cites this paper
• Migrastatics—Anti-metastatic and Anti-invasion Drugs: Promises and Challenges

  2017cites this paper
• Anti-metastatic and Anti-invasion Drugs: Promises and Challenges

  2017cites this paper
• Paving the Rho in cancer metastasis: Rho GTPases and beyond.

  2017cites this paper
• Targeting invasive properties of melanoma cells

  2017cites this paper
• Multicellular contractility contributes to the emergence of mesothelioma nodules

  2016cites this paper