Abstract 6564: Conversion of fibroblasts into Cancer-associated-fibroblasts (CAF) by small extracellular vesicles from EGFR mutated adenocarcinoma: Implication of SDC1 in the establishment of the lung premetastatic niche

Abstract 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) contribute to the establishment of a favourable microenvironment by the development of those niches. EVs and their contents have emerged as a potential source of information on tumour detection and regulatory drivers of tumour progression and metastasis. 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. Using PCR, we observed increased expression of fibroblast activation protein (FAP), COL1a1, MMP-2, and fibronectin in human lung fibroblasts treated with EVs derived from the EGFR-mutated cell line HCC827. 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. However, additional studies are required to precisely delineate these mechanisms. Citation Format: Amina Jouida, Cormac McCarthy, Michael P. Keane. Conversion of fibroblasts into Cancer-associated-fibroblasts (CAF) by small extracellular vesicles from EGFR mutated adenocarcinoma: Implication of SDC1 in the establishment of the lung premetastatic niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6564.