Matrix Stiffening and EGFR Cooperate to Promote the Collective Invasion of Cancer Cells

Abstract

In squamous cell carcinoma (SCC), tissue invasion by collectively invading cells requires physical forces applied by tumor cells on their surrounding extracellular matrix (ECM). Cancer-related ECM is composed of thick collagen bundles organized by carcinoma-associated fibroblasts (CAF) within the tumor stroma. Here, we show that SCC cell collective invasion is driven by the matrix-dependent mechano-sensitization of EGF signaling in cancer cells. Calcium (Ca) was a potent intracellular second messenger that drove actomyosin contractility. Tumor-derived matrix stiffness and EGFR signaling triggered increased intracellular Ca through Ca1.1 expression in SCC cells. Blocking L-type calcium channel expression or activity using Ca channel blockers verapamil and diltiazem reduced SCC cell collective invasion both and These results identify verapamil and diltiazem, two drugs long used in medical care, as novel therapeutic strategies to block the tumor-promoting activity of the tumor niche. This work demonstrates that calcium channels blockers verapamil and diltiazem inhibit mechano-sensitization of EGF-dependent cancer cell collective invasion, introducing potential clinical strategies against stromal-dependent collective invasion. http://cancerres.aacrjournals.org/content/canres/78/18/5229/F1.large.jpg .

Cancer stem‐like cells with hybrid epithelial/mesenchymal phenotype leading the collective invasion

“…Circulating tumor cell cluster formation involves collective cancer cell invasion, which has been the focus of many studies . Why do cancer cells collectively invade as a strand?…”

Interplay between Cell-Surface Receptors and Extracellular Matrix in Skin

“…From a pathological perspective, it is known that even moderate stiffening of the ECM sensitizes epithelial cells to EGF, allowing them to proliferate independently of their contact to neighboring cells-a mechanism which is a hallmark of cancer cells [361]. Accordingly, stiffening of the ECM is associated with tumor aggression, metastases and poor clinical outcome in various cancers [392,393]. Likewise, EGFR is frequently overexpressed or strongly activated in several tumor types and fuels tumorigenesis [394,395].…”

The Calcium-Signaling Toolkit in Cancer: Remodeling and Targeting

“…Mechanistically, in vitro studies implicate a change in focal adhesion protein turnover as a consequence of suppression of SOCE by ORAI1 and STIM1 silencing, resulting in the suppression of the motility and invasiveness capacity of cancer cells (Yang et al 2009). L-type voltagegated Ca 2+ channels were recently associated with collective migration of squamous cell carcinoma cells (Grasset et al 2018). At high con-centrations, diltiazem and verapamil, clinically used L-type Ca 2+ channel blockers, significantly reduce the invasive properties of patient-derived spheroid cultures, as well as invasion of squamous cell carcinoma patient-derived xenografts in an in vivo mouse model (Grasset et al 2018).…”

“…L-type voltagegated Ca 2+ channels were recently associated with collective migration of squamous cell carcinoma cells (Grasset et al 2018). At high con-centrations, diltiazem and verapamil, clinically used L-type Ca 2+ channel blockers, significantly reduce the invasive properties of patient-derived spheroid cultures, as well as invasion of squamous cell carcinoma patient-derived xenografts in an in vivo mouse model (Grasset et al 2018).…”