Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis
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 inter...
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| Format: | Article |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62486-3 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jeremy Williams |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e9ff02f82b994ef191cecf339a60125a |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e9ff02f82b994ef191cecf339a60125a2025-08-24T11:37:49ZengNature PortfolioNature Communications2041-17232025-08-0116111710.1038/s41467-025-62486-3Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesisJeremy Williams0Roman Camarda1Serghei Malkov2Lisa J. Zimmerman3Suzanne Manning4Dvir Aran5Andrew Beardsley6Daniel Van de Mark7Rachel Nakagawa8Yong Chen9Charles Berdan10Sharon M. Louie11Celine Mahieu12Daphne Superville13Juliane Winkler14Elizabeth Willey15Erica J. Hutchins16John D. Gagnon17Seda Kilinc Avsaroglu18Kosaku Shinoda19Matthew Gruner20Hiroshi Nishida21K. Mark Ansel22Zena Werb23Daniel K. Nomura24Shingo Kajimura25Atul J. Butte26Melinda E. Sanders27Daniel C. Liebler28Hope S. Rugo29Gregor Krings30John A. Shepherd31Andrei Goga32Department of Cell & Tissue Biology, University of California, San FranciscoDepartment of Cell & Tissue Biology, University of California, San FranciscoDepartment of Radiology & Biomedical Imaging, University of California, San FranciscoDepartment of Biochemistry, Vanderbilt University School of MedicineDepartment of Pathology, Vanderbilt University School of MedicineFaculty of Biology, Technion, Israel Institute of TechnologyDepartment of Cell & Tissue Biology, University of California, San FranciscoDepartment of Cell & Tissue Biology, University of California, San FranciscoDepartment of Cell & Tissue Biology, University of California, San FranciscoDepartment of Cell & Tissue Biology, University of California, San FranciscoDepartment of Chemistry, University of California, BerkeleyDepartment of Chemistry, University of California, BerkeleyDepartment of Cell & Tissue Biology, University of California, San FranciscoDepartment of Cell & Tissue Biology, University of California, San FranciscoDepartment of Anatomy, University of California, San FranciscoDepartment of Anatomy, University of California, San FranciscoDepartment of Cell & Tissue Biology, University of California, San FranciscoBiomedical Sciences Graduate Program, University of California, San FranciscoDepartment of Cell & Tissue Biology, University of California, San FranciscoDepartment of Cell & Tissue Biology, University of California, San FranciscoDepartment of Cell & Tissue Biology, University of California, San FranciscoDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Microbiology & Immunology, University of California, San FranciscoDepartment of Anatomy, University of California, San FranciscoDepartment of Chemistry, University of California, BerkeleyDepartment of Cell & Tissue Biology, University of California, San FranciscoFaculty of Biology, Technion, Israel Institute of TechnologyDepartment of Pathology, Vanderbilt University School of MedicineDepartment of Biochemistry, Vanderbilt University School of MedicineDepartment of Medicine, University of California, San FranciscoDepartment of Pathology, University of California, San FranciscoCancer Center, University of HawaiiDepartment of Cell & Tissue Biology, University of California, San FranciscoAbstract 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.https://doi.org/10.1038/s41467-025-62486-3 |
| spellingShingle | 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 Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis Nature Communications |
| title | Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis |
| title_full | Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis |
| title_fullStr | Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis |
| title_full_unstemmed | Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis |
| title_short | Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis |
| title_sort | tumor cell adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis |
| url | https://doi.org/10.1038/s41467-025-62486-3 |
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