Hippo Pathway Regulation and Microenvironmental Cues Governing Human MSC Transition to Cancer‐Associated Fibroblasts
TL;DR
Findings highlight YAP/TAZ as critical regulators of hMSC‐to‐CAF transformation, with implications for therapeutic strategies targeting tumor stroma.
Abstract
Cancer‐associated fibroblasts (CAFs) are key drivers of tumor progression. This study examined how three‐dimensional (3D) culture, hypoxia, and cancer‐derived soluble factors influence the transformation of human mesenchymal stem cells (hMSCs) into inflammatory CAFs (iCAFs). hMSCs from bone marrow, placenta, and chorion were cultured in 2D, in Matrigel‐based 3D systems, under hypoxia, and with soluble factors from colon cancer cells (HT29, HCT116). 3D culture strongly induced iCAF markers (IL1α, CSF3, IL6) while reducing myofibroblastic CAF markers (CCN2, MYL9, TAGLN). Hypoxia and cancer factors further enhanced this phenotype, promoting IL1α/IL6 secretion and shifting their influence from suppressing to stimulating cancer cell growth and angiogenesis. Mechanistically, these changes were associated with YAP/TAZ down‐regulation, and genetic depletion of YAP/TAZ alone was sufficient to convert hMSCs into iCAFs even in 2D culture. These findings highlight YAP/TAZ as critical regulators of hMSC‐to‐CAF transformation, with implications for therapeutic strategies targeting tumor stroma.