Cancer Cell Mechanics: Adhesion G Protein-coupled Receptors in Action?

Abstract

In mammals, numerous organ systems are equipped with adhesion G protein-coupled receptors (aGPCRs) to shape cellular processes including migration, adhesion, polarity and guidance. All of these cell biological aspects are closely associated with tumor cell biology. Consistently, aberrant expression or malfunction of aGPCRs has been associated with dysplasia and tumorigenesis. Mounting evidence indicates that cancer cells comprise viscoelastic properties that are different from that of their non-tumorigenic counterparts, a feature that is believed to contribute to the increased motility and invasiveness of metastatic cancer cells. This is particularly interesting in light of the recent identification of the mechanosensitive facility of aGPCRs. aGPCRs are signified by large extracellular domains (ECDs) with adhesive properties, which promote the engagement with insoluble ligands. This configuration may enable reliable force transmission to the ECDs and may constitute a molecular switch, vital for mechano-dependent aGPCR signaling. The investigation of aGPCR function in mechanosensation is still in its infancy and has been largely restricted to physiological contexts. It remains to be elucidated if and how aGPCR function affects the mechanoregulation of tumor cells, how this may shape the mechanical signature and ultimately determines the pathological features of a cancer cell. This article aims to view known aGPCR functions from a biomechanical perspective and to delineate how this might impinge on the mechanobiology of cancer cells.

Keywords: adhesion G protein-coupled receptors; cancer; cytoskeleton; extracellular matrix; mechanobiology.

Figure 1

Putative roles of adhesion G protein-coupled receptors (aGPCRs) in cancer. (A) Schematic illustration of a healthy cell without structural abnormalities and proper aGPCR function aligned with (B) a malignant cell signified by increased contractility, compliance, and extracellular matrix rigidity (28). These changes could intersect with aGPCR dysfunction and/or altered expression. Several aGPCRs have been shown to signal through RhoA (18, 29), which indirectly stimulates myosin-light chain phosphorylation (yellow) to promote acto-myosin contractility (F-actin and myosin in red and dark gray, respectively) (30). (C–E) Show different cellular properties previously associated with aGPCR function and malignancies; left panel: intact aGPCR function. Right panel: cellular deficits related to compromised aGPCR function/expression. (C) Schemes of differentiation hierarchy. Adult stem cells (indicated in red) renew themselves and produce progenitor cells (indicated in green), which go through several rounds of division before they differentiate into specialized cells (31). Compromised aGPCRs may promote a shift from differentiation to proliferation, which may cause progenitor cell expansion and benign or malignant tumorigenesis (right). (D) Cell and tissue polarity is fundamental for oriented cell division and tissue formation, processes that have been associated with aGPCR function (–34). (E) aGPCR malfunction often results in phenotypes linked to defective cell migration (–38). Defective cell-cell and cell-matrix adhesion of tumor cells may be causally associated with aGPCR dysfunction and catalyzes tumor cell migration and invasion.