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

Following exposure to chemoradiation, EAC cells increase their mitochondrial content and associated metabolic processes, which drives treatment resistance. Inhibition of this response using clinically applicable inhibitors of ESRRA in combination with (chemo)radiation shows promising anti-tumor activities and could be further developed for clinical use. We performed a transcriptomic assessment of pre- and post-treatment patient tissue samples by RNA-Seq, which was validated by immunohistochemistry. Cellular responses to chemoradiation were determined in patient-derived adherent tumor cell cultures exposed to an in vitro approximation of the CROSS regimen. Assessments of metabolic rewiring included bioinformatics, measurement of oxygen consumption and other metrics for mitochondrial fitness, transcriptomic analysis, fluorescence and electron microscopy. The identified metabolic pathway was then targeted by pharmacological and genetic tools in combination with (chemo)radiation in cell viability assays on adherent tumor cell cultures and organoids.