Extracellular vesicles secreted by triple negative breast cancer stem cells trigger pre-metastatic niche remodeling and metastatic growth in the lungs
Menée à l'aide de lignées cellulaires de cancer mammaire triple négatif et d'un modèle murin, cette étude met en évidence un mécanisme par lequel les vésicules extracellulaires des cellules souches cancéreuses augmentent le potentiel invasif des cellules cancéreuses et déclenchent la transformation des tissus pulmonaires sains en tissus permettant la croissance des métastases
Tumor secreted extracellular vesicles (EVs) are potent intercellular signaling platforms. They are responsible for the accommodation of the pre-metastatic niche (PMN) to support cancer cell engraftment and metastatic growth. However, complex cancer cell composition within the tumor increases also the heterogeneity among cancer secreted EVs subsets, a functional diversity that has been poorly explored. This phenomenon is particularly relevant in highly plastic and heterogenous Triple Negative Breast Cancer (TNBC), in which a significant representation of malignant cancer stem cells (CSCs) is displayed. Herein, we selectively isolated and characterized EVs from CSC or differentiated cancer cells (DCC) (EVsCSC and EVsDCC, respectively) from the MDA-MB-231 TNBC cell line. Our results showed that EVsCSC and EVsDCC contain distinct bioactive cargos and therefore elicit a differential effect on stromal cells in the TME. Specifically, EVsDCC activated secretory cancer associated fibroblasts (CAFs), triggering IL-6/IL-8 signaling and sustaining CSC phenotype maintenance. Complementarily, EVsCSC promoted the activation of α-SMA+ myofibroblastic CAFs subpopulations and increased the endothelial remodeling, enhancing the invasive potential of TNBC cells in vitro and in vivo. In addition, solely the EVsCSC mediated signaling prompted the transformation of healthy lungs into receptive niches able to support metastatic growth of breast cancer cells. This article is protected by copyright. All rights reserved.