Contact-based thymidylate transfer promotes collective tumor growth

Sustained cell proliferation is a fundamental hallmark of cancer, yet its mechanism remains elusive. While tumor cells often cooperate to enhance survival, the specific molecular forces driving this behavior are unknown. We uncover a novel mechanism of tumor growth, that cancer cells proliferate through a contact-dependent transfer of thymidylate (dTMP) via gap junctions with neighboring cells, bypassing canonical biosynthetic and salvage pathways driven by thymidylate synthase (TS) and thymidine kinase (TK1). Importantly, using a genetic mouse model of lung cancer harboring dual TS/TK1 tumor-specific knockout, we show that cancer cells lacking canonical synthesis maintain proliferation. These findings advance the current dogma of a ubiquitous nucleotide-driven activation in cancer, suggesting that a programmed dTMP re-equilibration sustains tumor growth. This novel mechanism could be exploited in cancer therapy. Overall design: Differential gene expression analysis for A549 cells with Cas9 mediated KO of TYMS (TS-KO) and TS-KO cells with restored proliferation in presence of parental A549 cells (TS-KO coculture)