Proteomic Characterization of MET-Amplified Esophageal Adenocarcinomas Reveals Enrichment of Alternative Splicing- and Androgen Signaling-Related Proteins

Background Esophageal adenocarcinomas (EACs) represent an evolving tumor entity with high mortality rates. MET amplification is a recurrent driver in EACs and is associated with decreased patient survival. However, the response to MET inhibitors is limited. Recent studies have identified several mechanisms that lead to resistance against MET inhibitors in different tumor entities. Nonetheless, a characterization of additional vulnerable targets beyond MET has not been conducted in MET-amplified EACs. Methods In this study, we determined the MET amplification status in a cohort of more than 900 EACs using fluorescence in situ hybridization (FISH) and compared the proteomes of MET-amplified versus non-amplified tumors by mass spectrometry. Results We identified a phenotype, present in almost all MET-amplified tumors, which shows an enrichment of alternative RNA splicing, and androgen receptor signaling proteins, as well as decreased patient survival. Additionally, our analyses revealed a negative correlation between MET expression and patient survival in MET-amplified EACs, indicating biological heterogeneity with clinical relevance despite the presence of MET amplification as the predominant oncogenic driver. Furthermore, quantitative immunohistochemical analysis of the inflammatory tumor microenvironment showed that an increased percentage of M2 macrophages is associated with lower overall survival in MET-amplified EACs. Conclusions Our results provide valuable insights into possible new therapeutic approaches for MET-amplified EACs for further research.

背景 食管腺癌（Esophageal adenocarcinomas, EACs）是一类进展中的肿瘤实体，死亡率居高不下。MET扩增是食管腺癌中反复出现的驱动事件，且与患者生存期缩短相关。不过，肿瘤对MET抑制剂的应答十分有限。既往研究已在多种肿瘤实体中阐明了数种MET抑制剂耐药的机制。然而，针对MET扩增型食管腺癌中MET以外的其他潜在治疗靶点的系统性表征工作仍未开展。
方法 本研究通过荧光原位杂交（fluorescence in situ hybridization, FISH）技术，对超过900例食管腺癌队列的MET扩增状态进行检测，并借助质谱技术比较了MET扩增型与非扩增型肿瘤的蛋白质组特征。
结果 本研究发现了一种几乎存在于所有MET扩增型肿瘤中的表型，该表型伴随可变RNA剪接与雄激素受体信号通路蛋白的富集，且与患者生存期缩短相关。此外，分析结果显示，在MET扩增型食管腺癌中，MET表达水平与患者生存期呈负相关，这表明尽管MET扩增作为主要致癌驱动因素存在，该类肿瘤仍具有临床相关性的生物学异质性。进一步的炎症性肿瘤微环境定量免疫组化分析表明，M2巨噬细胞占比升高与MET扩增型食管腺癌患者的总生存期缩短显著相关。
结论 本研究结果为MET扩增型食管腺癌的新型治疗策略开发提供了极具价值的理论依据，可为后续研究提供参考。