Tunneling nanotubes propagate a BMP-dependent preneoplastic state.

Tunneling nanotubes (TNTs) are thin, actin-based structures allowing long-distance communication between cells through the transfer of molecules and organelles. Although well-known to contribute to cancer progression, their role in early tumor initiation remains as yet unexplored. Here we address this question by using normal human mammary primary cells and an in-house human breast cell model recapitulating early luminal breast transformation. 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 phenotypic changes, including anchorage-independent growth. In particular, 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 and distant cells at the very onset of transformation, offering new perspectives on how epithelial transformation arises and spreads to neighboring cells.