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

Jeremy Williams, Roman Camarda, Serghei Malkov, Lisa J. Zimmerman, Suzanne Manning, Dvir Aran, Andrew Beardsley, Daniel Mark, Rachel Nakagawa, Yong Chen, Charles Berdan, Sharon M. Louie, Celine Mahieu, Daphne Superville, Juliane Winkler, Elizabeth Willey, Erica J. Hutchins, John D. Gagnon, Seda Kilinc Avsaroglu, Kosaku Shinoda, Matthew Gruner, Hiroshi Nishida, K. Mark Ansel, Zena Werb, Daniel K. Nomura, Shingo Kajimura, Atul J. Butte, Melinda E. Sanders, Daniel C. Liebler, Hope S. Rugo, Gregor Krings, John A. Shepherd and Andrei Goga ()
Additional contact information
Jeremy Williams: University of California, San Francisco
Roman Camarda: University of California, San Francisco
Serghei Malkov: University of California, San Francisco
Lisa J. Zimmerman: Vanderbilt University School of Medicine
Suzanne Manning: Vanderbilt University School of Medicine
Dvir Aran: Israel Institute of Technology
Andrew Beardsley: University of California, San Francisco
Daniel Mark: University of California, San Francisco
Rachel Nakagawa: University of California, San Francisco
Yong Chen: University of California, San Francisco
Charles Berdan: University of California, Berkeley
Sharon M. Louie: University of California, Berkeley
Celine Mahieu: University of California, San Francisco
Daphne Superville: University of California, San Francisco
Juliane Winkler: University of California, San Francisco
Elizabeth Willey: University of California, San Francisco
Erica J. Hutchins: University of California, San Francisco
John D. Gagnon: University of California, San Francisco
Seda Kilinc Avsaroglu: University of California, San Francisco
Kosaku Shinoda: University of California, San Francisco
Matthew Gruner: University of California, San Francisco
Hiroshi Nishida: Harvard Medical School
K. Mark Ansel: University of California, San Francisco
Zena Werb: University of California, San Francisco
Daniel K. Nomura: University of California, Berkeley
Shingo Kajimura: University of California, San Francisco
Atul J. Butte: Israel Institute of Technology
Melinda E. Sanders: Vanderbilt University School of Medicine
Daniel C. Liebler: Vanderbilt University School of Medicine
Hope S. Rugo: University of California, San Francisco
Gregor Krings: University of California, San Francisco
John A. Shepherd: University of Hawaii
Andrei Goga: University of California, San Francisco

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62486-3

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