Estrogen-related receptor alpha drives mitochondrial biogenesis and resistance to neoadjuvant chemoradiation in esophageal cancer

Dings, M. P.G. et al. (2022) Estrogen-related receptor alpha drives mitochondrial biogenesis and resistance to neoadjuvant chemoradiation in esophageal cancer. Cell Reports Medicine, 3(11), 100802. (doi: 10.1016/j.xcrm.2022.100802) (PMID:36334593) (PMCID:PMC9729822)

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Neoadjuvant chemoradiotherapy (nCRT) improves outcomes in resectable esophageal adenocarcinoma (EAC), but acquired resistance precludes long-term efficacy. Here, we delineate these resistance mechanisms. RNA sequencing on matched patient samples obtained pre-and post-neoadjuvant treatment reveal that oxidative phosphorylation was the most upregulated of all biological programs following nCRT. Analysis of patient-derived models confirms that mitochondrial content and oxygen consumption strongly increase in response to nCRT and that ionizing radiation is the causative agent. Bioinformatics identifies estrogen-related receptor alpha (ESRRA) as the transcription factor responsible for reprogramming, and overexpression and silencing of ESRRA functionally confirm that its downstream metabolic rewiring contributes to resistance. Pharmacological inhibition of ESRRA successfully sensitizes EAC organoids and patient-derived xenografts to radiation. In conclusion, we report a profound metabolic rewiring following chemoradiation and demonstrate that its inhibition resensitizes EAC cells to radiation. These findings hold broader relevance for other cancer types treated with radiation as well.

Item Type:Articles
Keywords:This work was supported by Oncode funding (to J.P.M.) and a KWF Dutch Cancer Society project grant (10992/2017-1) (to M.F.B. and H.W.M.v.L.).
Glasgow Author(s) Enlighten ID:Bailey, Dr Peter
Authors: Dings, M. P.G., van der Zalm, A. P., Bootsma, S., van Maanen, T. F.J., Waasdorp, C., van den Ende, T., Liu, D., Bailey, P., Koster, J., Zwijnenburg, D. A., Spek, C. A., Klomp, J. P.G., Oubrie, A., Hooijer, G. K.J., Meijer, S. L., van Berge Henegouwen, M. I., Hulshof, M. C., Bergman, J., Oyarce, C., Medema, J. P., van Laarhoven, H. W.M., and Bijlsma, M. F.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cell Reports Medicine
Publisher:Cell Press
ISSN (Online):2666-3791
Published Online:04 November 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Cell Reports Medicine 3(11):100802
Publisher Policy:Reproduced under a Creative Commons License

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