PI3K and MAPK signaling nodes as divergent drivers of phenotypic plasticity in cancer-associated fibroblasts in colorectal cancer

Cancer-associated fibroblasts (CAFs) exhibit phenotypic heterogeneity with each functional state playing critical roles in tumor progression. Notably, subtypes like inflammatory CAF (iCAF), characterized by increased chemokine/cytokine secretion, and myofibroblast-like CAF (myCAF), characterized by enhanced extracellular matrix (ECM) deposition and increased actomyosin contractility, can undergo phenotypic switching in response to cues from the tumor microenvironment (TME) and/or therapeutic interventions. However, the signaling pathways associated with their diverse phenotypes remain poorly understood. Through the analysis of single-cell RNA sequencing analysis of human colorectal cancer (CRC) we identified that the PI3K/mTOR and MAPK/ERK signaling pathways, among other pathways, are linked to the formation of myCAF and iCAF subtypes, respectively.In addition,we identified that PI3K/mTOR inhibition promotes the formation of iCAF through compensatory FGF-2 secretion and stimulation of the FGFR1-JAK2-STAT3 pathway; iCAF-derived chemokines/cytokines consequently enhance tumor spheroid growth and neutrophil infiltration.