A unique morphological phenotype in chemoresistant triple-negative breast cancer reveals metabolic reprogramming and PLIN4 expression as a molecular vulnerability

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

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

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 TNBCresistant 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.

Original languageEnglish
Pages (from-to)2492-2507
Number of pages16
JournalMolecular Cancer Research
Volume17
Issue number12
DOIs
Publication statusPublished - 2019
Externally publishedYes

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