Siddiqui, M. A.; Roemer, A. M. A.; Pinna, L.; Ramesh, V.; Moeller, S. S.; Gollavilli, P. N.; Turtos, A. M.; Varghese, S.; Guldborg, L. B.; Palani, N. P.; Napoli, F.; Volante, M.; Swietach, P.; Ceppi, P.

Sustained cell proliferation is a fundamental hallmark of cancer, yet its mechanism remains elusive, particularly in context of intercellular cooperation and metabolite exchange. We uncover a mechanism of tumor growth via collective proliferation, where a syncytium of cells connected by gap junctions allows dTMP equilibration and dispenses ubiquitous activation of canonical dTMP biosynthesis and salvage driven by thymidylate synthase (TYMS) and thymidine kinase 1 (TK1) respectively. Collective proliferation is observed in vitro and in clinical samples, and it is validated in a genetic mouse model of lung cancer harboring dual Tyms/Tk1 tumor-specific knockout, in which cells propel tumor progression despite lacking enzymatic dTMP synthesis, and the tumor growth is significantly mitigated by gap junction inhibition. These findings suggest that a programmed dTMP equilibration sustains collective tumor growth and revises the current dogma of a ubiquitous de novo activation. This mechanism could be exploited in cancer therapy.