A chemical biology screen reveals a role for Rab21-mediated control of actomyosin contractility in fibroblast-driven cancer invasion

Abstract

BACKGROUND: Carcinoma-associated fibroblasts (CAFs) can promote the progression of tumours in many ways. They can remodel the extracellular matrix to generate an environment that enables the invasion of cancer cells. We hypothesised that compounds that prevent matrix remodelling by CAFs would block their ability to promote carcinoma cell invasion. METHODS: We designed a screen for compounds that interfere with CAF-promoted matrix remodelling. Hits from this screen were investigated in organotypic invasion models of squamous cell carcinoma (SCC). RESULTS: We find that lovastatin and simvastatin reduce matrix remodelling by fibroblasts and thereby reduce SCC invasion. This class of compounds exert their effects partly through disrupting the function of Rab proteins, and we show a new role for Rab21 in promoting cancer cell invasion promoted by CAFs. CONCLUSIONS: Rab21 is required for CAFs to promote the invasion of cancer cells. It enables the accumulation of integrin a5 at the plasma membrane and subsequent force-mediated matrix remodelling.

Rho Kinase Inhibitors Block Melanoma Cell Migration and Inhibit Metastasis

“…1D). In order to strengthen the observation that CCT129254 and AT13148 are potent inhibitors of ROCK-driven actomyosin contractility, we assessed their effect on cell-induced contraction of collagen lattices (30). Results presented in Fig.…”

Chianina beef tenderness investigated through integrated Omics

“…1170) in the tender group (Table 3). By means of a molecular biology-based approach Hooper and colleagues [77] have indicated a role for Rab21 in mediating cancer invasion in a cellular model of carcinoma associated fibroblasts (CAFs) through driving control of the acto-myosin complex contractility via integrin alpha5 accumulation. This observation might be very likely transferred to the "muscle to meat conversion" scenario, where it influences (either increases or decreases) the capacity to trigger formation of the actomyosin complex post mortem and utterly results in shorter sarcomeres and tougher meat.…”

Extracellular matrix component signaling in cancer

“…Integrin-dependent MMP activity is likely to be involved as well as integrin-mediated contractile force. The close association between external and internal force in the context of tumour stroma has recently been highlighted in a study of squamous carcinomas [70]. A recent study documented a correlation between integrin α11 expression and LOXL1 activity in the tumour stroma [71].…”

“…A tissue-, tumour-and stagespecific induction of different MMPs accompanies this process. Some of the molecular details for these processes have been elucidated and shown to include RhoA, Rab21 and YAP [70,[76][77][78]. In an experimental 3D system in vitro human CAFs from ovarian carcinomas were found to express αv integrins and a limited set of β1 integrins [76].…”

“…Revealing in vitro studies have shown that integrins on contractile CAFs are an integrated part of tunneling of the matrix, paving the way for invading tumour cells [70,75]. A tissue-, tumour-and stagespecific induction of different MMPs accompanies this process.…”