A Unique Morphological Phenotype in Chemoresistant Triple-Negative Breast Cancer Reveals Metabolic Reprogramming and PLIN4 Expression as a Molecular Vulnerability
MOLECULAR CANCER RESEARCH
Authors: Sirois, Isabelle; Aguilar-Mahecha, Adriana; Lafleur, Josiane; Fowler, Emma; Viet Vu; Scriver, Michelle; Buchanan, Marguerite; Chabot, Catherine; Ramanathan, Aparna; Balachandran, Banujan; Legare, Stephanie; Przybytkowski, Ewa; Lan, Cathy; Krzemien, Urszula; Cavallone, Luca; Aleynikova, Olga; Ferrario, Cristiano; Guilbert, Marie-Christine; Benlimame, Naciba; Saad, Amine; Alaoui-Jamali, Moulay; Saragovi, Horace Uri; Josephy, Sylvia; O'Flanagan, Ciara; Hursting, Stephen D.; Richard, Vincent R.; Zahedi, Rene P.; Borchers, Christoph H.; Bareke, Eric; Nabavi, Sheida; Tonellato, Peter; Roy, Josee-Anne; Robidoux, Andre; Marcus, Elizabeth A.; Mihalcioiu, Catalin; Majewski, Jacek; Basik, Mark
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.
Whole genome and transcriptome sequencing of matched primary and peritoneal metastatic gastric carcinoma
SCIENTIFIC REPORTS
Authors: Zhang, J.; Huang, J. Y.; Chen, Y. N.; Yuan, F.; Zhang, H.; Yan, F. H.; Wang, M. J.; Wang, G.; Su, M.; Lu, G.; Huang, Y.; Dai, H.; Ji, J.; Zhang, J.; Zhang, J. N.; Jiang, Y. N.; Chen, S. J.; Zhu, Z. G.; Yu, Y. Y.
Abstract
Gastric cancer is one of the most aggressive cancers and is the second leading cause of cancer death worldwide. Approximately 40% of global gastric cancer cases occur in China, with peritoneal metastasis being the prevalent form of recurrence and metastasis in advanced disease. Currently, there are limited clinical approaches for predicting and treatment of peritoneal metastasis, resulting in a 6-month average survival time. By comprehensive genome analysis will uncover the pathogenesis of peritoneal metastasis. Here we describe a comprehensive whole-genome and transcriptome sequencing analysis of one advanced gastric cancer case, including non-cancerous mucosa, primary cancer and matched peritoneal metastatic cancer. The peripheral blood is used as normal control. We identified 27 mutated genes, of which 19 genes are reported in COSMIC database (ZNF208, CRNN, ATXN3, DCTN1, RP1L1, PRB4, PRB1, MUC4, HS6ST3, MUC17, JAM2, ITGAD, IREB2, IQUB, CORO1B, CCDC121, AKAP2, ACAN and ACADL), and eight genes have not previously been described in gastric cancer (CCDC178, ARMC4, TUBB6, PLIN4, PKLR, PDZD2, DMBT1and DAB1). Additionally, GPX4 and MPND in 19q13.3-13.4 region, is characterized as a novel fusion-gene. This study disclosed novel biological markers and tumorigenic pathways that would predict gastric cancer occurring peritoneal metastasis.
COA
Publication 
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