Research News

Tie2 activity in cancer associated myofibroblasts serves as novel target against reprogramming of cancer cells to embryonic-like cell state and associated poor prognosis in oral carcinoma patients

Myofibroblastic alpha-smooth muscle actin- (aSMA) positive cancer-associated fibroblasts (CAFs) in tumor stroma serve as potential indicator of poor-prognosis in oral cancer; but lack of understanding about the biology has limited our ability in development of effective treatment against CAFs. We have previously identified myofibroblastic C2-CAFs to be associated with increased stemness in oral cancer cells. Here, we show the role of autocrine or exogenous transforming growth factor beta (TGFb) in maintenance of C2-CAFs-like phenotypic and transcriptional state, which was mainly driven by TGFb-induced Tunica Interna Endothelial cell kinase 2- (Tie2) -signaling through histone deacetylase-mediated downregulation of its antagonist, Angiopoietin-2 in CAFs leading to phosphorylation of Tie2 (Y992) and subsequent activation of SRC (Y418). This led to SRC/ROCK mediated αSMA-positive stress-fiber formation with gain of myofibroblast phenotype. Further, to understand the functional relevance of Tie2-signaling in CAFs over cancer cells, we performed single-cell RNA sequencing (scRNA-Seq) of cancer cell co-cultured with un-induced, TGFb-induced or TGFb-induced-Tie2-inhibited CAFs. Distinct clustering of CAFs supported their transcriptional heterogeneity. Interestingly, the CAF-specific Tie2-signaling was responsible to promote embryonic-like reprogramming in cancer cells with increased stemness and EMT signatures. Inhibitor of Tie2-signaling in CAFs significantly abrogated the xenografts formation in zebrafish embryos and syngeneic allografts in mouse model of oral cancer cell lines. Remarkably, gene expression signatures derived from cancer cells co-cultured with Tie2-activated CAFs predicted poor prognosis in HNSCC patient of TCGA cohort. Thus, our work has provided wider applicability of Tie2-specific functions in tumor biology, along with its known role in endothelial cell-specific function. Mitra P, Saha U, Stephen KJ, Prasad P, Jena S, Patel AK, Bv H, Mondal SK, Kurkalang S, Roy S, Ghosh A, Roy SS, Das Sarma J, Biswas NK, Acharya M, Sharan R, Arun P, Jolly MK, Maitra A, Singh S. Tie2 activity in cancer associated myofibroblasts serves as novel target against reprogramming of cancer cells to embryonic-like cell state and associated poor prognosis in oral carcinoma patients. J Exp Clin Cancer Res. 2025 May 10;44(1):142. doi: 10.1186/s13046-025-03405-8.