Adipocyte-like signature in ovarian cancer minimal residual disease identifies metabolic vulnerabilities of tumor initiating cells

• DOI: 10.1172/jci.insight.147929
• Publication Date: 2021-05-04T16:04:42Z
• Authors: Mara Artibani; Kenta Masuda; Zhiyuan Hu; Pascal C. Rauher; Garry Mallett; Nina Wietek; Matteo Morotti; Kay Chong; Mohammad KaramiNe...; Christos E. Zois; Sunanda Dhar; Salma El-Sahhar; Leticia Campo; Sarah P. Blagden; Stephen Damato; Pubudu N. Pathiraja; Shibani Nicum; Fergus Gleeson; Alexandros Laios; Abdulkhaliq Alsaadi; Laura Santana Gon...; Takeshi Motohara; Ashwag Albukhari; Zhen Lu; Robert C. Bast Jr.; Adrian L. Harris; Christer S. Ejsing; Robin W. Klemm; Christopher Yau; Tatjana Sauka-Spe...; Ahmed A. Ahmed
• Keywords: Epithelial-Mesenchymal Transition; Neoplasm, Residual; Paclitaxel; Carcinoma, Ovarian Epithelial; Carboplatin; 03 medical and health sciences; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Adipocytes; Humans; Aged; Aged, 80 and over; Ovarian Neoplasms; 0303 health sciences; Fatty Acids; R; Cytoreduction Surgical Procedures; Middle Aged; Neoadjuvant Therapy; 3. Good health; Oncology; Neoplastic Stem Cells; Medicine; Female; Transcriptome; Oxidation-Reduction; Research Article

Similar to tumor-initiating cells (TICs), minimal residual disease (MRD) is capable of reinitiating tumors and causing recurrence. However, the molecular characteristics of solid tumor MRD cells and drivers of their survival have remained elusive. Here we performed dense multiregion transcriptomics analysis of paired biopsies from 17 ovarian cancer patients before and after chemotherapy. We reveal that while MRD cells share important molecular signatures with TICs, they are also characterized by an adipocyte-like gene expression signature and a portion of them had undergone epithelial-mesenchymal transition (EMT). In a cell culture MRD model, MRD-mimic cells showed the same phenotype and were dependent on fatty acid oxidation (FAO) for survival and resistance to cytotoxic agents. These findings identify EMT and FAO as attractive targets to eradicate MRD in ovarian cancer and make a compelling case for the further testing of FAO inhibitors in treating MRD.