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

  • Cell Rep Med. 2022 Nov 3;100802. doi: 10.1016/j.xcrm.2022.100802.
Mark P G Dings  1 ,  Amber P van der Zalm  2 ,  Sanne Bootsma  1 ,  Tatum F J van Maanen  2 ,  Cynthia Waasdorp  1 ,  Tom van den Ende  3 ,  Dajia Liu  3 ,  Peter Bailey  4 ,  Jan Koster  2 ,  Danny A Zwijnenburg  2 ,  C Arnold Spek  2 ,  Jan P G Klomp  5 ,  Arthur Oubrie  5 ,  Gerrit K J Hooijer  6 ,  Sybren L Meijer  6 ,  Mark I van Berge Henegouwen  7 ,  Maarten C Hulshof  8 ,  Jacques Bergman  9 ,  Cesar Oyarce  3 ,  Jan Paul Medema  1 ,  Hanneke W M van Laarhoven  10 ,  Maarten F Bijlsma  11
Affiliations
  • 1. Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands.
  • 2. Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands.
  • 3. Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam UMC Location University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands.
  • 4. School of Cancer Sciences, University of Glasgow, Glasgow, UK.
  • 5. Lead Pharma, Oss, the Netherlands.
  • 6. Amsterdam UMC Location University of Amsterdam, Department of Pathology, Amsterdam, the Netherlands.
  • 7. Amsterdam UMC Location University of Amsterdam, Department of Surgery, Amsterdam, the Netherlands.
  • 8. Amsterdam UMC Location University of Amsterdam, Department of Radiotherapy, Amsterdam, the Netherlands.
  • 9. Amsterdam UMC Location University of Amsterdam, Department of Gastroenterology, Amsterdam, the Netherlands.
  • 10. Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam UMC Location University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands.
  • 11. Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands. Electronic address: [email protected].
PMID: 36334593 DOI: 10.1016/j.xcrm.2022.100802
Abstract

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.

Keywords
ESRRA; chemoradiation; esophageal cancer; metabolic reprogramming; oxidative phosphorylation; radiation; resistance.
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