Regulation of FAP+ CAF expression and functional diversity by tumor microenvironment stiffness in breast cancer

Abstract

Cancer-associated fibroblasts (CAFs) are commonly correlated with unfavorable clinical prognosis. CAFs have been found to play a significant role in facilitating tumor growth through various mechanisms. Nevertheless, there is a lack of comprehensive knowledge regarding the specific impact of CAFs on tumor proliferation and the subsequent therapeutic outcomes. Discrepancies within this particular area of study may arise due to the heterogeneity seen in both the composition and function of fibroblasts inside the tumor microenvironment. Two distinct populations of mesenchymal cells expressing FAP were distinguished based on their expression of podoplanin (PDPN). These populations include a subset of FAP+ cells that also express PDPN, known as CAFs, and another subset of FAP+ cells that do not express PDPN, referred to as cancer-associated pericytes (CAPs). This study investigates the impact of conditioned media, TME stiffness, and the 4-day culture period on the activation and expression patterns of FAP+ CAFs. Our research aims to understand how varying TME stiffness affects FAP+ CAFs phenotypical expression. We analyze FAP expression correlation with traction forces on different substrates, unveiling the interplay between mechanical cues and FAP+ CAF. This investigation promises insights into CAF functional heterogeneity and adaptive responses to TME stiffness, which is crucial for refining cancer therapies. Understanding CAF dynamics in response to mechanical stimuli holds potential for optimizing TME-targeted therapies.