Mechanisms of Action of EGFR Tyrosine Kinase Receptor Incorporated in Extracellular Vesicles.
Zanetti-Domingues LC., Bonner SE., Martin-Fernandez ML., Huber V.
EGFR and some of the cognate ligands extensively traffic in extracellular vesicles (EVs) from different biogenesis pathways. EGFR belongs to a family of four homologous tyrosine kinase receptors (TKRs). This family are one of the major drivers of cancer and is involved in several of the most frequent malignancies such as non-small cell lung cancer, breast cancer, colorectal cancer and ovarian cancer. The carrier EVs exert crucial biological effects on recipient cells, impacting immunity, pre-metastatic niche preparation, angiogenesis, cancer cell stemness and horizontal oncogene transfer. While EV-mediated EGFR signalling is important to EGFR-driven cancers, little is known about the precise mechanisms by which TKRs incorporated in EVs play their biological role, their stoichiometry and associations to other proteins relevant to cancer pathology and EV biogenesis, and their means of incorporation in the target cell. In addition, it remains unclear whether different subtypes of EVs incorporate different complexes of TKRs with specific functions. A raft of high spatial and temporal resolution methods is emerging that could solve these and other questions regarding the activity of EGFR and its ligands in EVs. More importantly, methods are emerging to block or mitigate EV activity to suppress cancer progression and drug resistance. By highlighting key findings and areas that remain obscure at the intersection of EGFR signalling and EV action, we hope to cross-fertilise the two fields and speed up the application of novel techniques and paradigms to both.