Vallone, S. A.; Lara Montero, A.; Arcones, A. C.; Ruiz-Garrido, I.; Palavecino, M. D.; Montani, M. A.; Jimenez-Loygorri, J. I.; Nikolic, I.; Garcia Sola, M.; Leiva-Vega, L.; Leon, M.; Hermida, G. H.; Rodriguez, M. E.; Aguirre, P.; Maltagatti, D.; Flaks, D.; Jordanovski, N.; Querol, E. M.; Leguina, M. L.; Vornetti, S.; Acosta Haab, G.; Wertheimer, E.; Coso, O. A.; Schere-Levy, C.; Fededa, J. P.; de la Mata, M.; Kordon, E. C.; Sabio, G.; Gattelli, A.

Adipose tissue is the dominant stromal component of the breast, yet whether breast tumors exploit adipocyte plasticity to support cancer growth remains unclear. Here, we show that breast tumors actively disturb adipocyte differentiation, generating an immature tumor-adjacent adipose niche enriched in pre-adipocytes that directly promotes tumor progression. In human breast cancer samples, adipocytes located near tumors acquire a pre-adipocyte-like state. Functional studies demonstrate that pre-adipocytes enhance tumor cell proliferation both in vivo and in vitro. Mechanistically, we identify tumor-intrinsic RET signaling as a key regulator of this interaction. The RET receptor is a clinically relevant target expressed in breast cancer. RET drives a PDGF-B-dependent paracrine program that maintains pre-adipocytes in the tumor milieu. In turn, pre-adipocytes provide RET ligands that reinforce oncogenic signaling in tumor cells. Disruption of the RET-PDGF-B axis limits tumor progression. Together, our findings reveal an active tumor-driven mechanism by which breast tumors regulate adipocyte linage states to sustain growth and identify a novel targetable pathway controlling tumor-adipose tissue communication.