Treatment of esophageal cancer with chemotherapy and radiotherapy prior to surgery is not always helpful as many patients quickly develop resistance to treatment. A study from the groups of Maarten Bijlsma and Hanneke van Laarhoven published in the leading journal Cell Reports Medicine reports that one of the mechanisms of treatment resistance is increased mitochondrial biogenesis and cellular respiration driven by the transcription factor estrogen-related receptor alpha.

The standard treatment for esophageal cancers that can be surgically removed is radiation with chemotherapy beforehand (neoadjuvant chemoradiation). This approach has been shown to improve outcomes overall, but many patients quickly develop resistance that nullifies the effect of chemoradiation and, in some cases, increases the metastatic capacity of surviving cancer cells.

In a study funded by Dutch Cancer Society (KWF), PhD students Amber van der Zalm and Mark Dings compared the molecular profiles of tumors cells before and after treatment with chemoradiation, and saw that radiation of cancer cells causes an unexpected change in metabolism: a high increase in oxidative phosphorylation. Further analysis confirmed that mitochondrial content and oxygen consumption were strongly increased in response to ionizing radiation.

“We found that the irradiated cancer cells increased respiration – they ‘breathe’ more – and can use the extra energy to repair the damage from the radiation,” says researcher and shared first author Amber van der Zalm. “Therefore, the radiotherapy has less chance of killing the cells.”

Using bioinformatics, the researchers identified estrogen-related receptor alpha (ESRRA) as the transcription factor responsible for the profound metabolic rewiring. Importantly, inhibition of ESRRA in a preclinical model for esophageal cancer with drugs restored the sensitivity of the cancer cells to radiation, strongly inhibiting their growth.

These findings hold broader relevance for other cancer types treated with radiation as well.

“We know now that cancer cells harbor a remarkable flexibility that can affect numerous aspects of cellular metabolism,” says Mark Dings, shared first author on the publication.

“We are currently investigating the steps towards a clinical trial,” says Dr. Maarten Bijlsma. “We think that this study is an important contribution to improve the effect of radiotherapy not only for esophageal cancer, but also possibly other malignancies. The research and the possible subsequent applications are a good example of the kind of research that makes the Amsterdam UMC and Cancer Center Amsterdam unique and leading in the field of upper-GI cancers.”

For more information contact Dr. Maarten Bijlsma, or read the publication:

Dings, M.P.G., van der Zalm, A.P., et al. (2022) Estrogen-related receptor alpha drives mitochondrial biogenesis and resistance to neoadjuvant chemoradiation in esophageal cancer. Cell Reports Medicine. https://doi.org/10.1016/j.xcrm.2022.100802

People involved:

Mark P.G. Dings

Amber P. van der Zalm

Sanne Bootsma

Tatum F.J. van Maanen

Cynthia Waasdorp

Tom van den Ende

Dajia Liu

Peter Bailey

Jan Koster

Danny A. Zwijnenburg

C. Arnold Spek

Jan P.G. Klomp

Arthur Oubrie

Gerrit K.J. Hooijer

Sybren L. Meijer

Mark I. van Berge Henegouwen

Maarten C. Hulshof

Jacques Bergman

Cesar Oyarce

Jan Paul Medema

Hanneke W.M. van Laarhoven

Maarten F. Bijlsma

Funding

The study was funded by the Dutch Cancer Society (KWF) and the ONCODE institute

This article was created for Cancer Center Amsterdam.

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