Identification of progenitor cells that drive Interleukin 11-dependent tumor-stroma coevolution in advanced melanoma [TGFB_bulkRNAseq]

Tumor mesenchymal stem cells (TMSCs) orchestrate tumor microenvironment (TME) transformation via their ability to transdifferentiate. Metastatic solid tumors often feature neural crest-like/mesenchymal phenotypes characterized by high expression levels of TGFβ-dependent epithelial-to-mesenchymal transition (EMT) and EMT-like programs. Specifically, EMT-like endothelial-to-mesenchymal (EndMT) programs are responsible for the differentiation of TMSCs towards cancer-associated fibroblasts (CAFs). CAFs dictate tumor progression, invasiveness, and immune evasion. Exploring the molecular determinants of CAFs generation and pathobiology is thus of paramount importance to improve therapy response. The in vitro responses of patient-derived TMSCs were investigated upon recapitulating TGFβ-driven EMT-like TME traits. The resulting myofibroblastic CAFs (myCAFs) originated from TMSCs via EndMT were characterized by enhanced Interleukin-11 (IL11) expression and secretion. We propose IL11+ myCAFs as a driver of the tumor-stromal crosstalk responsible for the pro-tumorigenic, mesenchymal, angiogenic, and immunosuppressive TME transformation in metastatic melanoma.