Neoadjuvant chemotherapy (NAC) followed by surgery is a standard approach for management of locally advanced esophageal squamous cell carcinoma (ESCC). Patients who do not respond well to NAC have a poor prognosis. Despite extensive research, the mechanisms of chemoresistance in ESCC remain largely unknown. Here, we established paired tumor organoids—designated as PreNAC-O and PostNAC-O—from one ESCC patient before and after NAC, respectively. Although the two organoids did not exhibit significant differences in proliferation, morphology or drug sensitivity in vitro, the tumorigenicity of PostNAC-O in vivo was significantly higher than that of PreNAC-O. Xenografts from PreNAC-O tended to exhibit keratinization, while those from PostNAC-O displayed conspicuous necrotic areas. The tumorigenicity of PostNAC-O xenografts during the chemotherapy was comparable to that of PreNAC-O without treatment. Furthermore, the gene expression profiles of the xenografts suggested that expression of genes involved in the EMT and/or hypoxia response might be related to the tumorigenicity of PostNAC-O. Our data suggested that the tumorigenicity of residual cancer had been enhanced, outweighing the effects of chemotherapy, rather than being attributable to intrinsic chemoresistance. Further studies are required to clarify the extent to which residual cancers share a common mechanism similar to that revealed here.

新辅助化疗（NAC）随后进行手术是治疗局部晚期食管鳞状细胞癌（ESCC）的标准方法。对 NAC 反应不佳的患者预后较差。尽管进行了广泛的研究，食管鳞癌的化疗耐药机制仍然很大程度上未知。在这里，我们分别从 NAC 之前和之后的一名 ESCC 患者身上建立了配对的肿瘤类器官，称为 PreNAC-O 和 PostNAC-O。尽管两种类器官在体外的增殖、形态或药物敏感性方面没有表现出显着差异，但PostNAC-O的体内致瘤性明显高于PreNAC-O。PreNAC-O 的异种移植物倾向于表现出角化，而 PostNAC-O 的异种移植物则表现出明显的坏死区域。化疗期间PostNAC-O异种移植物的致瘤性与未经治疗的PreNAC-O相当。此外，异种移植物的基因表达谱表明，参与 EMT 和/或缺氧反应的基因表达可能与 PostNAC-O 的致瘤性有关。我们的数据表明，残留癌的致瘤性已经增强，超过了化疗的效果，而不是归因于内在的化疗耐药性。需要进一步的研究来阐明残留癌症在多大程度上具有与此处揭示的相似的共同机制。