Fig. 2

CAFs promote resistance to anti-cancer therapies through paracrine signals and mutual metabolic reprogramming. Upon exposure to a therapeutic insult, CAFs support an adaptive response in cancer cells that ultimately leads to therapy failure. a) Drug treatment triggers NF-kB and JAK/STAT signaling in CAFs. CAFs-released paracrine signals include exosome-mediated delivery of mRNAs and ncRNAs and a broad range of cytokines (mainly interleukins and growth factors). Activated pathways in cancer cells include pro-survival, anti-apoptotic and stemness programs. Signaling loops are depicted with rectangular-shaped arrows. b) As a mechanism of mutual adaptation to low levels of glutamine and glucose, CAFs provide metabolites that boost mitochondrial metabolism in cancer cells, hence fueling a resistant phenotype. Metabolites can also function as signaling molecules, as for the lactate secreted by cancer cells that induces NF-kB-mediated transcription in CAFs, which results in secretion of HGF that mediates TKIs resistance