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. Overall design: 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.

食管腺癌细胞（Esophageal Adenocarcinoma, EAC）在接受放化疗暴露后，其线粒体含量与关联代谢过程均会上调，进而驱动治疗耐药性的产生。采用临床可用的ESRRA抑制剂（Estrogen-Related Receptor Alpha, ESRRA）联合（放）化疗抑制该应答，已展现出颇具潜力的抗肿瘤活性，有望进一步推进至临床转化。

实验整体设计：本研究通过RNA测序（RNA-Seq）对患者治疗前后的组织样本开展转录组学评估，并以免疫组织化学实验对结果进行验证。在患者来源的贴壁肿瘤细胞培养物中，本研究检测了细胞对放化疗的应答反应，该培养物暴露于体外模拟的CROSS治疗方案。

代谢重编程的相关评估涵盖生物信息学分析、氧消耗量测定及其他线粒体健康相关指标检测、转录组学分析，以及荧光显微镜与电子显微镜观察。随后，本研究通过药理学与遗传学工具，联合（放）化疗，在贴壁肿瘤细胞培养物及类器官的细胞活力实验中，对所鉴定出的代谢通路进行靶向干预。