Fig. 9

CAF-specific Tie2 activity in reprogramming of oral cancer cells. We have previously identified and characterized C1-CAF and C2-CAF in oral cancer. C1-CAFs exhibit higher-BMP4 expression, whereas C2-CAF exhibit myofibroblastic phenotype with aSMA-positive stress fiber formation. The C2-CAFs supported stem-like properties in cancer cells. Here, we have explored the possible mechanism and demonstrated that the TGFβ-induced myofibroblastic differentiation and conversion of C1-CAF into C2-CAF is mediated through the activation of Tie2-signaling with suppression of its antagonist-ANGPT2 due to HDAC-mediated deacetylation of its promoter. Furthermore, Tie2-inhibition was found to convert TGFβ-induced-CAF towards the transcriptional state of C1-CAF. Functionally, TGFβ-induced CAF reprogramed oral cancer cells into embryonic-like state with enhanced stemness and EMT properties. Emphasizing its clinical translational value, the specific gene-signature derived from the cancer cells, reprogrammed by TGFβ-induced Tie2-activated-CAF, may predict the poor prognosis in head and neck cancer patients