A Unique Morphological Phenotype in Chemoresistant Triple-Negative Breast Cancer Reveals Metabolic Reprogramming and PLIN4 Expression as a Molecular Vulnerability.

Eric Bareke, Amine Saad, Moulay Alaoui-Jamali, Horace Uri Saragovi, Sylvia Josephy, Ciara O'Flanagan, Stephen D Hursting, Vincent R Richard, René P Zahedi, Christoph H Borchers, Naciba Benlimame, Sheida Nabavi, Peter Tonellato, Josée-Anne Roy, André Robidoux, Elizabeth A Marcus, Catalin Mihalcioiu, Jacek Majewski, Mark Basik, Banujan Balachandran, Adriana Aguilar-Mahecha, Josiane Lafleur, Emma Fowler, Viet Vu, Michelle Scriver, Marguerite Buchanan, Catherine Chabot, Aparna Ramanathan, Isabelle Sirois, Stéphanie Légaré, Ewa Przybytkowski, Cathy Lan, Urszula Krzemien, Luca Cavallone, Olga Aleynikova, Cristiano Ferrario, Marie-Christine Guilbert

Journal: Molecular cancer research : MCR 2020;17(12):2492-2507

PMID: 31537618

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Abstract

The major obstacle in successfully treating triple-negative breast cancer (TNBC) is resistance to cytotoxic chemotherapy, the mainstay of treatment in this disease. Previous preclinical models of chemoresistance in TNBC have suffered from a lack of clinical relevance. Using a single high dose chemotherapy treatment, we developed a novel MDA-MB-436 cell-based model of chemoresistance characterized by a unique and complex morphologic phenotype, which consists of polyploid giant cancer cells giving rise to neuron-like mononuclear daughter cells filled with smaller but functional mitochondria and numerous lipid droplets. This resistant phenotype is associated with metabolic reprogramming with a shift to a greater dependence on fatty acids and oxidative phosphorylation. We validated both the molecular and histologic features of this model in a clinical cohort of primary chemoresistant TNBCs and identified several metabolic vulnerabilities including a dependence on PLIN4, a perilipin coating the observed lipid droplets, expressed both in the TNBC-resistant cells and clinical chemoresistant tumors treated with neoadjuvant doxorubicin-based chemotherapy. These findings thus reveal a novel mechanism of chemotherapy resistance that has therapeutic implications in the treatment of drug-resistant cancer. IMPLICATIONS: These findings underlie the importance of a novel morphologic-metabolic phenotype associated with chemotherapy resistance in TNBC, and bring to light novel therapeutic targets resulting from vulnerabilities in this phenotype, including the expression of PLIN4 essential for stabilizing lipid droplets in resistant cells.

Address: Segal Cancer Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Québec, Canada.; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.; Department of Oncology and Surgery, McGill University, Montréal, Québec, Canada.; Hôpital Maisonneuve Rosemont, Département de pathologie et biologie cellulaire, Université de Montréal, Québec, Canada.; Lady Davis Institute-Jewish General Hospital; Center for Translational Research, McGill University, Montréal, Québec, Canada.; Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.; Integrated Program for Neuroscience, McGill University, Montréal, Québec, Canada.; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; University of North Carolina Nutrition Research Institute, Kannapolis, North Carolina.; Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.; Gerald Bronfman Department of Oncology, Jewish General Hospital, McGill University, Montréal, Québec, Canada.; University of Victoria Genome British Columbia Proteomics Centre, University of Victoria, Victoria, Canada.; McGill University and Genome Québec Innovation Center, Montréal, Québec, Canada.; Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts.; Hôpital du Sacre Coeur, Montreal, Québec, Canada.; Centre Hospitalier de l'Université de Montreal, Montreal, Québec, Canada.; John H. Stroger Jr. Hospital, Chicago, Illinois.; McGill University Hospital Center, Montreal, Québec, Canada.; Department of Human Genetics, McGill University, Montréal, Québec, Canada.; Segal Cancer Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Québec, Canada. [email protected].

DOI: 10.1158/1541-7786.MCR-19-0264