Breast cancer mammospheres secrete Adrenomedullin to induce lipolysis and browning of adjacent adipocytes

Autor: Cédric Y. Darini, Samah Rekima, Mark Basik, B. Chignon-Sicard, Simon Lachambre, Virginie Virolle, Xi Yao, Martin Paré, Annie Ladoux, Christian Dani, Adriana Aguilar-Mahecha
Přispěvatelé: Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Segal Cancer Centre, Lady Davis Institute, Université Côte d'Azur (UCA), Division of Experimental Medicine [Montréal, QC, Canada] (Department of Medicine), McGill University Health Center [Montreal] (MUHC)
Rok vydání: 2020
Předmět:
Zdroj: BMC Cancer, Vol 20, Iss 1, Pp 1-15 (2020)
BMC Cancer
BMC Cancer, BioMed Central, 2020, 20 (1), pp.784. ⟨10.1186/s12885-020-07273-7⟩
ISSN: 1471-2407
DOI: 10.1186/s12885-020-07273-7
Popis: Background Cancer cells cooperate with cells that compose their environment to promote tumor growth and invasion. Among them, adipocytes provide lipids used as a source of energy by cancer cells and adipokines that contribute to tumor expansion. Mechanisms supporting the dynamic interactions between cancer cells and stromal adipocytes, however, remain unclear. Methods We set-up a co-culture model with breast cancer cells grown in 3D as mammospheres and human adipocytes to accurately recapitulate intrinsic features of tumors, such as hypoxia and cancer cell–adipocytes interactions. Results Herein, we observed that the lipid droplets’ size was reduced in adipocytes adjacent to the mammospheres, mimicking adipocyte morphology on histological sections. We showed that the uncoupling protein UCP1 was expressed in adipocytes close to tumor cells on breast cancer histological sections as well as in adipocytes in contact with the mammospheres. Mammospheres produced adrenomedullin (ADM), a multifactorial hypoxia-inducible peptide while ADM receptors were detected in adipocytes. Stimulation of adipocytes with ADM promoted UCP1 expression and increased HSL phosphorylation, which activated lipolysis. Invalidation of ADM in breast cancer cells dramatically reduced UCP1 expression in adipocytes. Conclusions Breast tumor cells secreted ADM that modified cancer–associated adipocytes through paracrine signaling, leading to metabolic changes and delipidation. Hence, ADM appears to be crucial in controlling the interactions between cancer cells and adipocytes and represents an excellent target to hinder them.
Databáze: OpenAIRE
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