Tunneling nanotubes propagate a BMP-dependent preneoplastic state

Tunneling nanotubes (TNTs) are thin, actin-based structures allowing long-distance communication between cells by promoting the transfer of molecules and organelles. Well-known to contribute to cancer progression, we investigated their role in early tumor initiation using an in-house human breast cell model recapitulating early transformation. We observed that TNTs become more abundant and elongated during this process, and preferentially connect transformed donor cells to non-transformed acceptor cells. We show that this long-range, directional communication involves the transfer of the signaling receptor BMPR1b. Within days, this transfer induces gene expression changes in acceptor cells, consistent with early transformation programs. Functional analyses of these acceptor cells revealed metabolic rewiring and phenotypic changes, including anchorage-independent growth. Moreover, the transferred BMPR1b receptor sensitized acceptor cells to BMP2 signals present in the microenvironment, amplifying their transformation potential. Hence, by tracking the earliest molecular responses in acceptor cells, we deciphered the initial steps of a transformation cascade triggered by TNT-mediated transfer. These findings uncover a BMP-dependent mechanism by which transformed cells propagate a preneoplastic state to adjacent cells at the onset of transformation, offering new perspectives on how epithelial transformation arises and spreads to neighboring cells.