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.

Structure of BAI1/ELMO2 complex reveals an action mechanism of adhesion GPCRs via ELMO family scaffolds

“…aGPCRs are widely expressed and play critical roles in cell adhesion, cell polarity and cell migration 2,4,5 . Abnormalities of aGPCRs have been linked with various human diseases including cancers 6,7 , immunological diseases 8 , nephrotic syndrome 9 , and psychiatric disorders 10 , etc.…”

The Mechanical Microenvironment in Breast Cancer

“…For example, the g-protein coupled receptor (GPCR) GPR68 has recently been identified as a novel sensor of fluid flow necessary for vascular physiology [ 210 ], and may be an emerging therapeutic target in cancer [ 211 ]. Mechanically sensitive adhesion GPCRs [ 212 ] are another set of potential targets, such as GPR116 which can promote actomyosin contractility and breast cancer metastasis [ 213 ]. Furthermore, immune cell mechanosensing is a rapidly evolving field [ 214 ] that may represent an indirect mechanism in breast cancer progression, as it could also be modified by enhanced mechanosignaling in the tumor microenvironment.…”

Opportunities and challenges for drug discovery in modulating Adhesion G protein-coupled receptor (GPCR) functions

“…The aGPCR family is believed to be involved in cancer through multiple mechanisms, including tumor angiogenesis [126,127] and tumor cell migration/invasion [128,129] modulation. The aGPCR ECD interactions are also believed to be implicated in tumorigenic activity, possibly through their hallmark adhesive properties that affect the tumor cells viscoelasticity [130].…”