Cooperation and Interplay between EGFR Signalling and Extracellular Vesicle Biogenesis in Cancer

Abstract

Epidermal growth factor receptor (EGFR) takes centre stage in carcinogenesis throughout its entire cellular trafficking odyssey. When loaded in extracellular vesicles (EVs), EGFR is one of the key proteins involved in the transfer of information between parental cancer and bystander cells in the tumour microenvironment. To hijack EVs, EGFR needs to play multiple signalling roles in the life cycle of EVs. The receptor is involved in the biogenesis of specific EV subpopulations, it signals as an active cargo, and it can influence the uptake of EVs by recipient cells. EGFR regulates its own inclusion in EVs through feedback loops during disease progression and in response to challenges such as hypoxia, epithelial-to-mesenchymal transition and drugs. Here, we highlight how the spatiotemporal rules that regulate EGFR intracellular function intersect with and influence different EV biogenesis pathways and discuss key regulatory features and interactions of this interplay. We also elaborate on outstanding questions relating to EGFR-driven EV biogenesis and available methods to explore them. This mechanistic understanding will be key to unravelling the functional consequences of direct anti-EGFR targeted and indirect EGFR-impacting cancer therapies on the secretion of pro-tumoural EVs and on their effects on drug resistance and microenvironment subversion.

Keywords: EV biogenesis; EV heterogeneity; MVB heterogeneity; endocytosis; epidermal growth factor receptor (EGFR); extracellular vesicles (EVs); microenvironment subversion; therapy resistance; tumour microenvironment.

Figure 1

(A) Cartoon of EGF-bound EGFR dimer showing the extracellular back-to-back dimer [16,17] and the intracellular asymmetric tyrosine kinase dimer [18]. The latter leads to phosphorylation of C-terminal tyrosines and recruitment of effectors; (B) (i–iii) Ligand-free head-to-head, stalk-to-stalk and back-to-back dimers [5]. (iv) Ligand-bound tetramer. The open-ended scheme allows the formation of longer oligomers [4].

Figure 2

An EGFR-centric view of EV biogenesis. This cartoon describes the possible routes taken by EGFR in its journey through and out of the cell. Top panel: degradative pathway at high EGF dose (left), retrieval at low dose (middle), and recycling (right). Endoplasmic reticulum (ER) contacts with tubular buds, which lead to EGFR dephosphorylation by PTPB1, are also shown. Possible EGFR structures and relevant endocytic effectors are depicted in each location. Red frames highlight the different known pathways of EV biogenesis involving EGFR and its ligands, namely the ARF6-linked microvesicle pathway at the plasma membrane (bottom left), the classical exosome pathway involving sorting at the MVB (bottom middle) and the cancer-specific Large Oncosome pathway (bottom right).

Figure 3

Pathway diagram of EGFR post-endocytic fate.