![]() ESRRA is associated with mitochondrial biogenesis in EAC These effectively prevented the upregulation of mitochondrial copy numbers, suggesting the ROS induced by ionizing radiation drives the increased mitochondrial response in EAC cells ( Figure 2G). Next, this time frame was used for perturbation experiments with antioxidants N-acetyl cysteine (NAC), and the mitochondrially targeted MitoQ. We then defined the temporal dynamics of mitochondrial upregulation in response to radiation alone, and found that this was achieved within several days ( Figure S2G). This indicates that ROS production from radiation is acute and that this modality of the CR regimen is likely the driver of mitochondrial biogenesis. ROS were measured using a chemical probe and we observed that brief exposure to ionizing radiation induces ROS levels that approach those resulting from long-term CR ( Figure S2F). Of note, surviving cells showed an altered morphology, as reported by us previously.Īnd we investigated this interconnection by measurements and perturbations of ROS. This was also found by transmission electron microscopy ( Figure 2E, high magnifications of mitochondrial morphology shown in Figure S2C). Confocal microscopy of dye-labeled mitochondria in treatment naive and chemoradiated 289B cells showed an increase of mitochondrial content in treated cells ( Figure 2D). Conversely, basal ECAR levels and measurements of glycolysis pathway transcripts showed a reduction in response to CR ( Figures S2A and S2B). Mitochondrial stress testing revealed that respiration was increased, in particular maximal respiration ( Figures 2B and 2C). Graphical abstractĪnalysis of baseline oxygen consumption rate over extracellular acidification rate (ECAR) (a measure of lactate production through glycolysis) by Seahorse flux analysis showed a clear shift in bioenergetic flux toward oxidative phosphorylation following CR in almost all esophageal cell lines ( Figure 2A ). These findings hold broader relevance for other cancer types treated with radiation as well. In conclusion, we report a profound metabolic rewiring following chemoradiation and demonstrate that its inhibition resensitizes EAC cells to radiation. Pharmacological inhibition of ESRRA successfully sensitizes EAC organoids and patient-derived xenografts to radiation. 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. 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. 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. ![]() Here, we delineate these resistance mechanisms. Neoadjuvant chemoradiotherapy (nCRT) improves outcomes in resectable esophageal adenocarcinoma (EAC), but acquired resistance precludes long-term efficacy. ![]()
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