Conférence | A journey within the tumor microenvironment reveals STAT3 as a central hub for fibroblast activation in epidermoid carcinomas – Cédric Gaggioli

A journey within the tumor microenvironment reveals STAT3 as a central hub for fibroblast activation in epidermoid carcinomas.

A key determinant for sSCC metastatic progression relies in the intricate interplay between cancer cells and tumor microenvironment. Carcinoma-associated fibroblasts (CAF) profoundly impact cancer aggressiveness by orchestrating the tumor ecosystem. Two major sub-populations of CAF, the myofibroblastic CAF (myCAF) and the inflammatory CAF (iCAF) coexist in the sSCC TME. While CAF heterogeneity has gained recognition as an essential factor in cancer progression, it is yet a compelling challenge to understand their heterogenous biogenesis and multifaceted functions.

To decipher the molecular mechanisms of CAF heterogeneity, biogenesis, and functions, we have engineered a CRISPR-Cas9 competent human fibroblast population, from primary cells, that enables flow cytometry and microscopy real-time tracking of their differentiation into either myCAF (myCAF promoter driving GFP) or iCAF (iCAF promoter driving BFP). Mechanistically, we demonstrate by genes expression analysis and functional assays, that human cSCC cells secrete pro-inflammatory cytokines that convert human skin fibroblasts into iCAF preferentially. We identified pharmacological inhibitors that restores the ability of cSCC cells to induce dermal fibroblast differentiation into myCAF. We show that myCAF and iCAF have differential functional activities on the TME remodeling. Our data suggest that in the tumor microenvironment (TME) of squamous cell carcinoma (sSCC), iCAF and myCAF cooperate to orchestrate the TEM and tumor agressivness.