Journal Article

Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis

Kajimura, Shingo, Krings, Gregor, Van de Mark, Daniel, Malkov, Serghei, Superville, Daphne, Gruner, Matthew, Ansel, K. Mark, Camarda, Roman, Nishida, Hiroshi, Butte, Atul J., Rugo, Hope S., Nakagawa, Rachel, Nomura, Daniel K., Goga, Andrei, Aran, Dvir, Berdan, Charles, Chen, Yong, Manning, Suzanne, Shinoda, Kosaku, Avsaroglu, Seda Kilinc, Liebler, Daniel C., Louie, Sharon M., Zimmerman, Lisa J., Williams, Jeremy, Mahieu, Celine, Shepherd, John A., Willey, Elizabeth, Werb, Zena, Winkler, Juliane, Beardsley, Andrew, Hutchins, Erica J., Sanders, Melinda E., Gagnon, John D.

2025

Overview

A pro-tumorigenic role for adipocytes has been identified in breast cancer, and reliance on fatty acid catabolism found in aggressive tumors. The molecular mechanisms by which tumor cells coopt neighboring adipocytes, however, remain incompletely understood. Here, we describe a direct interaction linking tumorigenesis to adjacent adipocytes. We examine breast tumors and their normal adjacent tissue from several patient cohorts, patient-derived xenografts, and mouse models, and find that lipolysis and lipolytic signaling are activated in neighboring adipose tissue. We find that functional gap junctions form between breast cancer cells and adipocytes. As a result, cAMP is transferred from breast cancer cells to adipocytes and activates lipolysis in a gap junction-dependent manner. We find that connexin 31 ( GJB3 ) promotes receptor triple negative breast cancer growth and activation of lipolysis in vivo. Thus, direct tumor cell-adipocyte interaction contributes to tumorigenesis and may serve as a new therapeutic target in breast cancer. Breast cancer cells interact with neighbouring adipocytes, but the mechanisms are not fully understood. Here, the authors show that triple-negative breast cancer (TNBC) cells transfer cAMP through gap junctions, activating lipolysis in tumour-associated adipocytes to promote TNBC growth.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/95 / 14/35 / 14/63 / 631/67/1347 / 631/67/2327 / Adipocytes / Adipocytes - metabolism / Adipocytes - pathology / Adipose tissue / Adipose Tissue - metabolism / Animal models / Animals / Body fat / Breast cancer / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Carcinogenesis - metabolism / Carcinogenesis - pathology / Catabolism / Cell Communication / Cell Line, Tumor / Connexins / Connexins - genetics / Connexins - metabolism / Cyclic AMP / Cyclic AMP - metabolism / Cytokines / Fatty acids / Female / Gap junctions / Gap Junctions - metabolism / Gene expression / Humanities and Social Sciences / Humans / Lipids / Lipolysis / Mammography / Mice / Molecular modelling / multidisciplinary / Patients / Proteins / Science / Science (multidisciplinary) / Signal Transduction / Therapeutic targets / Tissues / Triple Negative Breast Neoplasms - metabolism / Triple Negative Breast Neoplasms - pathology / Tumor cells / Tumorigenesis / Tumors / Xenotransplantation