Tumor cell-adipocyte gap junctions activate lipolysis and are essential for breast tumorigenesis

Camarda, R.; Williams, J.; Malkov, S.; Zimmerman, L. J.; Manning, S.; Aran, D.; Beardsley, A.; Van de Mark, D.; Chen, Y.; Berdan, C. A.; Louie, S. M.; Mahieu, C.; Winkler, J.; Willey, E.; Gagnon, J. D.; Shinoda, K.; Ansel, K. M.; Werb, Z.; Nomura, D. K.; Kajimura, S.; Butte, A. J.; Sanders, M. E.; Liebler, D. C.; Rugo, H.; Krings, G.; Shepherd, J. A.; Goga, A.

doi:10.1101/277939

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bioRxiv · 10.1101/277939

Tumor cell-adipocyte gap junctions activate lipolysis and are essential for breast tumorigenesis

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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 elusive. 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 identify connexin 31 (GJB3), which 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. One sentence summaryGap junctions between breast cancer cells and adipocytes transfer cAMP and activate lipolysis in the breast tumor microenvironment to support growth.

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Camarda, R., Williams, J., Malkov, S., Zimmerman, L. J., Manning, S., Aran, D., Beardsley, A., Van de Mark, D., Chen, Y., Berdan, C. A., Louie, S. M., Mahieu, C., Winkler, J., Willey, E., Gagnon, J. D., Shinoda, K., Ansel, K. M., Werb, Z., Nomura, D. K., Kajimura, S., Butte, A. J., Sanders, M. E., Liebler, D. C., Rugo, H., Krings, G., Shepherd, J. A., Goga, A.. 2018-03-07. Tumor cell-adipocyte gap junctions activate lipolysis and are essential for breast tumorigenesis. https://doi.org/10.1101/277939

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