TY - JOUR
T1 - Adipocyte-like signature in ovarian cancer minimal residual disease identifies metabolic vulnerabilities of tumorinitiating cells
AU - Artibani, Mara
AU - Masuda, Kenta
AU - Hu, Zhiyuan
AU - Rauher, Pascal C.
AU - Mallett, Garry
AU - Wietek, Nina
AU - Morotti, Matteo
AU - Chong, Kay
AU - Ranjbar, Mohammad Karami Nejad
AU - Zois, Christos E.
AU - Dhar, Sunanda
AU - El-Sahhar, Salma
AU - Campo, Leticia
AU - Blagden, Sarah P.
AU - Damato, Stephen
AU - Pathiraja, Pubudu N.
AU - Nicum, Shibani
AU - Gleeson, Fergus
AU - Laios, Alexandros
AU - Alsaadi, Abdulkhaliq
AU - Gonzalez, Laura Santana
AU - Motohara, Takeshi
AU - Albukhari, Ashwag
AU - Lu, Zhen
AU - Bast, Robert C.
AU - Harris, Adrian L.
AU - Ejsing, Christer S.
AU - Klemm, Robin W.
AU - Yau, Christopher
AU - Sauka-Spengler, Tatjana
AU - Ahmed, Ahmed Ashour
N1 - Funding Information:
We thank the Oncology Clinical Trials Office of the University of Oxford, Karl Morten, and Katrina Gads-by for technical assistance and the Nuffield Department of Clinical Neurosciences and Connor Scott for the access to the laser capture microscope. This work was funded by Ovarian Cancer Action, NIHR Oxford Biomedical Research Centre, Cancer Research UK Oxford Centre, and the MD Anderson Specialized Program of Research Excellence in Ovarian Cancer from the National Cancer Institute, NIH (P50CA217685, RCB, ZL, and AAA). This research was supported by the VILLUM Foundation (VKR023439, CSE), the VILLUM Center for Bioanalytical Sciences (VKR023179, CSE), and the Lundbeckfonden (R54-A5858, CSE). KM was supported by Japan Society for the Promotion of Science Overseas Research Fellowships, a fellowship from the Uehara Memorial Foundation, and an overseas study grant from the Kanzawa Medical Research Foundation.
Publisher Copyright:
© 2021, Artibani et al.
PY - 2021/6/8
Y1 - 2021/6/8
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.147929
DO - 10.1172/jci.insight.147929
M3 - Article
C2 - 33945502
AN - SCOPUS:85107393257
SN - 2379-3708
VL - 6
JO - JCI insight
JF - JCI insight
IS - 11
M1 - e147929
ER -
