Fibroblast Activation into Cancer-Associated Fibroblasts by Small Extracellular Vesicles from EGFR-Mutated Adenocarcinoma: The Role of SDC1 in Lung Premetastatic Niche Formation

Evidence across several cancer types supports the existence of metastasis-supportive microenvironments, called the premetastatic niche (PMN) which form at sites of future metastasis, allowing the colonization and growth of disseminated tumour cells. Extracellular vesicles (EVs) play a crucial role in shaping these niches. Recently, we have demonstrated that EVs are mediators of EMT and tumour invasion. We reported that EVs derived from serum of patients with EGFR mutated non-small cell lung cancer (NSCLC) mediates the activation of the PI3K/AKT/mTOR pathway and induce an invasion in epithelial cells through the up-regulation of MMP-9 by promoting partial EMT. This study aims to investigate the impact of EVs on fibroblasts, another key component of the PMN. PCR analysis revealed increased expression of fibroblast activation markers (FAP, COL1a1, MMP-2, and fibronectin) in lung fibroblasts treated with EVs from the EGFR-mutated HCC827 cell line. Functional assays revealed that these EV-treated fibroblasts exhibited enhanced invasive and migratory abilities, as shown through a modified Boyden chamber assay and a wound healing assay. We also showed that the knock-out of SDC-1 prevents the activation of fibroblast by sEVs. Additionally, in an indirect co-culture system, epithelial cells exposed to EVs were capable of activating and recruiting fibroblasts. Our results suggest that EVs derived from EGFR-mutated adenocarcinoma serum could be a potential contributor to the establishment of a favourable metastatic microenvironment through the remodelling of the stroma. This may provide insights into the mechanisms of lung cancer progression and metastasis.