PDPN+ CAFs facilitate the motility of OSCC cells by inhibiting ferroptosis via transferring exosomal lncRNA FTX

Abstract

Abstract Cancer-associated fibroblasts (CAFs) are abundant and heterogeneous in tumor microenvironment. Cross-talk between cancer cells and CAFs results in cancer progression. Here, we demonstrated that a distinct cancer-associated fibroblasts with podoplanin (PDPN) positive expression (PDPN+ CAFs) was correlated with poor survival in oral squamous cell carcinoma (OSCC). PDPN+ CAFs promoted the progression of OSCC by transferring exosomal lncRNA FTX to OSCC cells. Mechanistically, FTX bound to flap endonuclease-1 (FEN1), forming an RNA‒protein complex. FTX enhanced promoter demethylation of FEN1 by recruiting ten-eleven translocation-2 (TET2). In addition, FTX/FEN1 axis promoted OSCC cells motility by inhibiting ferroptosis. In xenograft experiments, RSL-3, a ferroptosis-inducing agent, suppressed the tumorigenesis potential of FEN1-overexpressed OSCC cells. Furthermore, ACSL4 was confirmed to participate in the motility promotion induced by FEN1 overexpression. FEN1 could bound to promoter region of Acyl-CoA synthetase long-chain family member 4 (ACSL4) and then inhibit ferroptosis in OSCC cells. Our study reveals that PDPN+ CAFs promote the invasiveness of OSCC cells by inhibiting ferroptosis through FTX/FEN1/ACSL4 signaling cascade. PDPN+ CAFs may serve as a novel potential therapeutic target for OSCC.