Nature Communications (Aug 2025)
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 Van de 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,
- Andrei Goga
Affiliations
- Jeremy Williams
- Department of Cell & Tissue Biology, University of California, San Francisco
- Roman Camarda
- Department of Cell & Tissue Biology, University of California, San Francisco
- Serghei Malkov
- Department of Radiology & Biomedical Imaging, University of California, San Francisco
- Lisa J. Zimmerman
- Department of Biochemistry, Vanderbilt University School of Medicine
- Suzanne Manning
- Department of Pathology, Vanderbilt University School of Medicine
- Dvir Aran
- Faculty of Biology, Technion, Israel Institute of Technology
- Andrew Beardsley
- Department of Cell & Tissue Biology, University of California, San Francisco
- Daniel Van de Mark
- Department of Cell & Tissue Biology, University of California, San Francisco
- Rachel Nakagawa
- Department of Cell & Tissue Biology, University of California, San Francisco
- Yong Chen
- Department of Cell & Tissue Biology, University of California, San Francisco
- Charles Berdan
- Department of Chemistry, University of California, Berkeley
- Sharon M. Louie
- Department of Chemistry, University of California, Berkeley
- Celine Mahieu
- Department of Cell & Tissue Biology, University of California, San Francisco
- Daphne Superville
- Department of Cell & Tissue Biology, University of California, San Francisco
- Juliane Winkler
- Department of Anatomy, University of California, San Francisco
- Elizabeth Willey
- Department of Anatomy, University of California, San Francisco
- Erica J. Hutchins
- Department of Cell & Tissue Biology, University of California, San Francisco
- John D. Gagnon
- Biomedical Sciences Graduate Program, University of California, San Francisco
- Seda Kilinc Avsaroglu
- Department of Cell & Tissue Biology, University of California, San Francisco
- Kosaku Shinoda
- Department of Cell & Tissue Biology, University of California, San Francisco
- Matthew Gruner
- Department of Cell & Tissue Biology, University of California, San Francisco
- Hiroshi Nishida
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School
- K. Mark Ansel
- Department of Microbiology & Immunology, University of California, San Francisco
- Zena Werb
- Department of Anatomy, University of California, San Francisco
- Daniel K. Nomura
- Department of Chemistry, University of California, Berkeley
- Shingo Kajimura
- Department of Cell & Tissue Biology, University of California, San Francisco
- Atul J. Butte
- Faculty of Biology, Technion, Israel Institute of Technology
- Melinda E. Sanders
- Department of Pathology, Vanderbilt University School of Medicine
- Daniel C. Liebler
- Department of Biochemistry, Vanderbilt University School of Medicine
- Hope S. Rugo
- Department of Medicine, University of California, San Francisco
- Gregor Krings
- Department of Pathology, University of California, San Francisco
- John A. Shepherd
- Cancer Center, University of Hawaii
- Andrei Goga
- Department of Cell & Tissue Biology, University of California, San Francisco
- DOI
- https://doi.org/10.1038/s41467-025-62486-3
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 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.
