Tunneling nanotubes propagate a BMP-dependent preneoplastic state.
Tunneling nanotubes (TNTs) are thin, actin-rich structures that facilitate long-distance intercellular communication through the transfer of molecules and organelles. While their role in cancer progression is well-established, their involvement in the earliest stages of tumor initiation remains unexplored. Using normal human mammary primary cells, a model of early luminal breast transformation, and mammary organoids, we demonstrate that TNTs become increasingly abundant and elongated during the initial phases of luminal breast cell transformation. Notably, these structures preferentially connect transformed donor cells to non-transformed acceptor cells, establishing an horizontal communication network, favoring the direction of transfer from transformed to non transformed cells. Unbiased proteomics and single-cell RNA sequencing analyses, coupled with (correlative) super-resolution microscopy reveal that, through this network, transformed cells transfer key molecular signals to non-transformed acceptor cells, inducing changes of their proteome and transcriptome landscape within days. Further analyses of acceptor cells reveal dysregulation of the BMP pathway, including increased expression of the Bone Morphogenetic Protein receptor type 1b (BMPR1b), together with functional phenotypic alterations such as the acquisition of anchorage-independent growth, a hallmark of preneoplastic progression. Our findings highlight how TNT-mediated transfer initiates a BMP-dependent cascade of molecular and phenotypic changes in acceptor cells, effectively propagating preneoplastic cues. By elucidating these early events, our findings provide new mechanistic insights into the onset of epithelial transformation in luminal breast cancer, identify the BMP pathway as a key mediator of this process, and advance our understanding of how preneoplastic states emerge and disseminate.