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.
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.
Cell Rep Med. 2022 Nov 15;3(11):100802. doi: 10.1016/j.xcrm.2022.100802. Epub 2022 Nov 4.
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.
新辅助放化疗（nCRT）可改善可切除食管腺癌（EAC）的预后，但获得性耐药会妨碍长期疗效。在此，我们描述了这些耐药机制。对新辅助治疗前后获得的匹配患者样本进行 RNA 测序显示，氧化磷酸化是 nCRT 后所有生物学程序中上调最明显的。对患者来源模型的分析证实，线粒体含量和耗氧量在 nCRT 后强烈增加，电离辐射是致病因素。生物信息学鉴定出雌激素相关受体 alpha（ESRRA）是负责重编程的转录因子，ESRRA 的过表达和沉默功能证实其下游代谢重排有助于耐药。ESRRA 的药理学抑制可成功使 EAC 类器官和患者来源异种移植物对辐射敏感。总之，我们报告了化疗放疗后发生的深刻代谢重排，并证实其抑制可使 EAC 细胞对辐射重新敏感。这些发现对其他接受放疗治疗的癌症类型也具有更广泛的意义。
