Gain Fat—Lose Metastasis: Converting Invasive Breast Cancer Cells into Adipocytes Inhibits Cancer Metastasis

• Published in: Cancer cell Vol. 35; no. 1; pp. 17 - 32.e6
• Main Authors: Ishay-Ronen, Dana, Diepenbruck, Maren, Kalathur, Ravi Kiran Reddy, Sugiyama, Nami, Tiede, Stefanie, Ivanek, Robert, Bantug, Glenn, Morini, Marco Francesco, Wang, Junrong, Hess, Christoph, Christofori, Gerhard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.01.2019
• Subjects: adipocyte; adipogenesis; breast cancer; cell plasticity; differentiation therapy; EMT; invasion; metastasis; TGFβ-signaling; trans-differentiation; adipogenesis; TGFβ-signaling; invasion; metastasis; adipocyte; trans-differentiation; breast cancer; cell plasticity; differentiation therapy; EMT
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2018.12.002

Cancer cell plasticity facilitates the development of therapy resistance and malignant progression. De-differentiation processes, such as an epithelial-mesenchymal transition (EMT), are known to enhance cellular plasticity. Here, we demonstrate that cancer cell plasticity can be exploited therapeutically by forcing the trans-differentiation of EMT-derived breast cancer cells into post-mitotic and functional adipocytes. Delineation of the molecular pathways underlying such trans-differentiation has motivated a combination therapy with MEK inhibitors and the anti-diabetic drug Rosiglitazone in various mouse models of murine and human breast cancer in vivo. This combination therapy provokes the conversion of invasive and disseminating cancer cells into post-mitotic adipocytes leading to the repression of primary tumor invasion and metastasis formation. [Display omitted] •EMT-derived breast cancer cells can differentiate into post-mitotic adipocytes•Adipogenesis disconnects cancer cells from an invasive and oncogenic phenotype•EMT/MET transcription factors and TGF-β signaling regulate cancer adipogenesis•Adipogenesis-inducing drug combinations repress metastasis in preclinical models Ronen et al. show that the cellular plasticity of cancer cells undergoing EMT can be exploited to force trans-differentiation of breast cancer cells into post-mitotic and functional adipocytes, leading to the repression of primary tumor invasion and metastasis formation.