上皮间质转化 (EMT) 已被确定为治疗耐药的驱动因素，特别是在食管腺癌 (EAC) 中，转化生长因子 β (TGF-β) 可以诱导这一过程。 TGF-β 抑制剂可能会抵消化疗（放疗）治疗后间充质耐药肿瘤细胞群的发生，并改善 EAC 的治疗结果。在这里，我们的目的是确定对 TGF-β 靶向反应的预测生物标志物。新辅助治疗的体外近似值适用于公开可用的原代 EAC 细胞系。采用 TGF-β 抑制剂 fresolimumab 和 A83-01 抑制 EMT，并通过流式细胞术定量间充质标志物以评估疗效。我们的结果表明，放化疗后间充质细胞状态得到了强有力的诱导，抑制 TGF-β 导致间充质标志物出现不同程度的减少。细胞系分为有反应者和无反应者。通过RNA-seq分析获得基因组表达谱。差异表达基因 (DEG) 分析确定了 10 个正相关中心基因和 23 个负相关中心基因，并通过生物信息学方法进行了鉴定。此外，使用公共药物基因组数据库检查了 DEG 与 TGF-β 抑制反应的相关性，揭示了 9 个正相关 DEG 和 11 个负相关 DEG。其中，ERBB2、EFNB1 和 TNS4 是最有希望的候选者。我们的研究结果揭示了化疗（放射）EAC 中与 TGF-β 抑制反应相关的独特基因表达模式。确定的 DEG 和预测标记可能有助于在研究 TGF-β 靶向的临床研究中选择患者。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

Epithelial-mesenchymal transition (EMT) has been identified as a driver of therapy resistance, particularly in esophageal adenocarcinoma (EAC), where transforming growth factor beta (TGF-β) can induce this process. Inhibitors of TGF-β may counteract the occurrence of mesenchymal, resistant tumor cell populations following chemo(radio)therapy and improve treatment outcomes in EAC. Here, we aimed to identify predictive biomarkers for the response to TGF-β targeting. In vitro approximations of neoadjuvant treatment were applied to publicly available primary EAC cell lines. TGF-β inhibitors fresolimumab and A83-01 were employed to inhibit EMT, and mesenchymal markers were quantified via flow cytometry to assess efficacy. Our results demonstrated a robust induction of mesenchymal cell states following chemoradiation, with TGF-β inhibition leading to variable reductions in mesenchymal markers. The cell lines were clustered into responders and non-responders. Genomic expression profiles were obtained through RNA-seq analysis. Differentially expressed gene (DEG) analysis identified 10 positively- and 23 negatively-associated hub genes, which were bioinformatically identified. Furthermore, the correlation of DEGs with response to TGF-β inhibition was examined using public pharmacogenomic databases, revealing 9 positively associated and 11 negatively associated DEGs. Among these, ERBB2, EFNB1, and TNS4 were the most promising candidates. Our findings reveal a distinct gene expression pattern associated with the response to TGF-β inhibition in chemo(radiated) EAC. The identified DEGs and predictive markers may assist patient selection in clinical studies investigating TGF-β targeting.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.