Exosomes from EGFR-mutated adenocarcinoma induce a partial/hybrid EMT

Abstract

Exosomes, a class of extra cellular vesicles with sizes ranging from 30-150nm, have emerged as a potential source of information on tumour detection and regulatory drivers of tumour progression and metastasis. They have been reported to influence epithelial mesenchymal transition (EMT) in pathological states such as metastatic lung cancer.

We analysed the effects of exosomes derived from an Epidermal Growth Factor Receptor (EGFR) mutated cell line (HCC827) and from serum of different lung cancer patients: EGFR-mutated adenocarcinoma, wild-type adenocarcinoma, squamous and serum of patient with no cancer on cells from an A549 cell line.

We observed by zymography that only exosomes derived from EGFR-mutated adenocarcinoma patients and from the EGFR mutated cell line induced an increase in pro-MMP9 and MMP9 activity in A549 cells. MMPs are one of the major attributes that epithelial cells acquire after undergoing EMT. Moreover, we showed that EGFR-mutated exosomes treatment increases the invasive capacity and the migratory capacity of A549 and HBE4 E6/E7 cells.

We observed a significant increase of vimentin expression, a mesenchymal marker while retaining the epithelial characteristics as evidenced by the unaltered levels of E-cadherin and EPCAM. EMT is not a binary process but instead, cells often exhibit a spectrum of epithelial/mesenchymal phenotype(s). Such hybrid cells can move collectively as clusters which is thought to enhance their invasive properties. We observed an increase of markers of hybrid-EMT and collective migration.

Our results suggest that exosomes derived from EGFR-mutated adenocarcinoma serum could be a potential mediator of hybrid-EMT and tumour invasion.