Soft matrices downregulate FAK activity to promote growth of tumor-repopulating cells

Abstract

Tumor-repopulating cells are a tumorigenic sub-population of cancer cells that drives tumorigenesis. We have recently reported that soft fibrin matrices maintain tumor-repopulating cell growth by promoting histone 3 lysine 9 (H3K9) demethylation and Sox2 expression and that Cdc42 expression influences H3K9 methylation. However, the underlying mechanisms of how soft matrices induce H3K9 demethylation remain elusive. Here we find that tumor-repopulating cells exhibit lower focal adhesion kinase (FAK) and H3K9 methylation levels in soft fibrin matrices than control melanoma cells on 2D rigid substrates. Silencing FAK in control melanoma cells decreases H3K9 methylation, whereas overexpressing FAK in tumor-repopulating cells enhances H3K9 methylation. Overexpressing Cdc42 or RhoA in the presence of FAK knockdown restores H3K9 methylation levels. Importantly, silencing FAK, Cdc42, or RhoA promotes Sox2 expression and proliferation of control melanoma cells in stiff fibrin matrices, whereas overexpressing each gene suppresses Sox2 expression and reduces growth of TRCs in soft but not in stiff fibrin matrices. Our findings suggest that low FAK mediated by soft fibrin matrices downregulates H3K9 methylation through reduction of Cdc42 and RhoA and promotes growth of tumor-repopulating cells.

Cdc42-dependent modulation of rigidity sensing and cell spreading in tumor repopulating cells

“…In integrin-mediated mechanotransduction, downstream focal adhesion kinase (FAK) is one of the molecules that controls Cdc42 activity [32]. Recently, downregulation of FAK has been reported to regulate histone 3 lysine residue 9 (H3K9) demethylation via Cdc42 [33], providing a potential link between Cdc42 and TRC self-renewal. However, the role of Cdc42 in translating outside physical cues into meaningful intracellular signals and its contribution to regulating cell spreading and self-renewal was not well understood.…”

The roles of nuclear focal adhesion kinase (FAK) on Cancer: a focused review

“…For example, via Src-FAK-STAT3 signaling, IL-6 induces VEGF-C expressions [17]. As a result, FAK kinase activity is required for tumor growth [18], angiogenesis [17], and vascular permeability [19]. These show that FAK is a typical multifunctional protein which integrates and transduces signals into cancer cells via integrin or growth factor receptors.…”

Regulation of immune-related diseases by multiple factors of chromatin, exosomes, microparticles, vaccines, oxidative stress, dormancy, protein quality control, inflammation and microenvironment: a meeting report of 2017 International Workshop of the Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine on Tumor Immunology

“…Dr. Wang revealed that cell deformability is a key factor in the control of extravasation dynamics during cancer metastasis 55 . His findings demonstrate the critical roles of mechanotransduction and mechanobiology in stem cell biology and cancer cell biology 56 , 57 . Dr. Wang proposed that mechanobiology-based medicine (mechanobiomedicine or mechanomedicine) 58 is poised to emerge as an exciting branch of medicine that uses mechanics-based principles and engineering-based technologies for novel diagnostics and therapeutics of diseases.…”