Deciphering of intra‐tumoural heterogeneity and the interplay between metastasis‐associated meta‐program and myofibroblasts in gastric cancer

作者：Xiongyan Wu, Zhijian Jin, Baolong Li, Yifan Lu, Junyi Hou, Lizhong Yao, Zhenjia Yu, Qingqing Sang, Beiqin Yu, Jianfang Li, Chen Li, Chao Yan, Zhenggang Zhu, Kaiwen Tang, Bingya Liu, Liping Su · 发表于：Clinical and Translational Medicine · 年份：2025 · DOI：10.1002/ctm2.70319 · 被引用次数：11 · 研究领域：Single-cell and spatial transcriptomics、Cancer Cells and Metastasis、Cancer Immunotherapy and Biomarkers

BACKGROUND: Gastric cancer (GC) exhibits high heterogeneity that relies on the oncogenic properties of cancer cells and multicellular interactions in the tumour microenvironment. However, the heterogeneity of GC and their molecular characteristics are still largely unexplored. METHODS: We employed single-cell and spatial transcriptomics to comprehensively map the intra-tumoural heterogeneity within GC. Additionally, in vitro experiments, clinical sample analyses, and patient-derived organoid models (PDOs) were conducted to validate the key interaction patterns between tumor cells and stromal cells. RESULTS: Seven robust meta-programs (MP1-MP7) in GC were defined with distinct biological significance and spatial distributions. MP3 and MP4 were intimately associated with distinct CD8 T cells skewed toward a cytotoxic or exhaustion state, while MP7, characterised by the highest degree of malignancy, harboured an immune lockdown microenvironment around it and spatially associated with myofibroblasts (myCAFs). Notably, we clarified the interplay between the MP7 and myCAFs, where MP7 induces the chemotactic migration of fibroblasts and promoting their transformation into myCAFs via GDF15/TGFBR2, and in turn, myCAFs-derived RSPO3 up-regulates EGR1 to promote the transformation to MP7 in GC cells and human PDOs. Ultimately, the accumulation of myCAFs around MP7 led to fewer infiltration of CD8 T cells, resulting an immune-deprived microenvironment and the diminished efficacy of immun...