MCM10, a novel YAP1/TEAD4 target, drives gastric cancer progression by bridging DNA replication to stemness acquisition

作者：Fuda Xie, Hoi Wing Leung, Yang Lyu, Peiyao Yu, Tiejun Feng, Bonan Chen, Jialin Wu, Jenson A. Tham, Canbin Fang, Alvin Hk Cheung, Chit Chow, Jianhui Jiang, Jintao Hu, Fengbin Zhang, Chaowei Zhu, Keli Zhong, Meiheng Sun, Ge Zhang, Sifan Yu, Dazhi Xu, Shouyu Wang, Bing Huang, Zhuang Kangmin, Xiaobei Luo, Aimin Li, Qing Guo, Chanchan Gao, Bin Zhang, Yuan Ma, William KK Wu, Liwei An, Chi Chun Wong, Jun Yu, Ka Fai To, Wei Kang · 发表于：Molecular Cancer · 年份：2026 · DOI：10.1186/s12943-026-02623-8 · 被引用次数：1 · 研究领域：Hippo pathway signaling and YAP/TAZ、RNA Research and Splicing、Congenital heart defects research

OBJECTIVES: Gastric cancer (GC) remains a major global health challenge, with chemotherapy resistance significantly hindering treatment efficacy. A significant proportion of chemotherapeutics impact DNA replication, yet the mechanisms by which tumors evade this lethality remain incompletely understood. Notably, minichromosome maintenance 10 replication initiation factor (MCM10) is pivotal in initiating DNA replication, holding promise in mediating acquired chemotherapy resistance. This work aims to elucidate the driving roles of MCM10 GC pathogenesis and chemotherapeutic resistance. METHODS: The expression pattern of MCM10 and its clinical relevance in GC patients were investigated by adopting single-cell RNA-seq data and in-house GC tissue microarray. Functional roles were evaluated through bioinformatic analyses and experimental assays, including in vivo xenograft formation assay and patient-derived organoid (PDO) models. The transcriptional regulation of MCM10 by the YAP1-TEAD4 complex was examined via Yap1−/−;Taz−/− transgenic mice models and functional rescue assays. Candidates for targeting MCM10 were predicted by virtual screening and further validated by cellular thermal shift assay (CETSA). RESULTS: MCM10 was the most upregulated MCM family member in GC cell lines, and its elevated levels correlated with poor patient prognosis. Bioinformatic analysis linked MCM10 to DNA replication and DNA damage repair, a finding confirmed by functional assays showing that MCM10 dep...