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

Mara Artibani, Kenta Masuda, Zhiyuan Hu, Pascal C. Rauher, Garry Mallett, Nina Wietek, Matteo Morotti, Kay Chong, Mohammad Karami Nejad Ranjbar, 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 AlsaadiLaura Santana Gonzalez, Takeshi Motohara, Ashwag Albukhari, Zhen Lu, Robert C. Bast, Adrian L. Harris, Christer S. Ejsing, Robin W. Klemm, Christopher Yau, Tatjana Sauka-Spengler, Ahmed Ashour Ahmed*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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.

Original languageEnglish
Article numbere147929
JournalJCI Insight
Volume6
Issue number11
ISSN2379-3708
DOIs
Publication statusPublished - 8. Jun 2021

Bibliographical note

Publisher Copyright:
© 2021, Artibani et al.

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