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

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-04-28 DOI:10.1002/ctm2.70319

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

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引用次数: 0

Abstract

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 immunotherapy. Additionally, based on the gene expression signatures of MP7 GC cells, we predicted specific drugs and verified more potent inhibitory effects of Taselisib and Lapatinib for MP7 GC cells than conventional drugs at the same concentration.

Conclusion

Taken together, these results deepened the understanding of GC heterogeneity and paved the way for novel therapeutic strategies by targeting MP7 GC cells and their interaction loop with myCAFs in GC treatment.

Key points

Seven robust meta-programs (MP1-MP7) were identified in gastric cancer.
MP7 was strongly correlated with cancer metastasis and poor survival of gastric cancer patients.
MP7 promoted fibroblast transformation into myCAFs via GDF15/TGFBR2, creating an immune lockdown microenvironment.
MyCAFs induced MP7 transformation via the RSPO3/EGR1 pathway, promoting gastric cancer cell migration.
Taselisib and Lapatinib were potent inhibitors of MP7 GC cells.

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胃癌肿瘤内异质性及转移相关元程序与肌成纤维细胞之间的相互作用

胃癌（GC）表现出高度的异质性，这取决于癌细胞的致癌特性和肿瘤微环境中的多细胞相互作用。然而，GC的异质性及其分子特性在很大程度上仍未被探索。方法采用单细胞转录组学和空间转录组学方法综合绘制胃癌肿瘤内异质性。此外，通过体外实验、临床样本分析和患者来源的类器官模型（PDOs）来验证肿瘤细胞和基质细胞之间的关键相互作用模式。结果GC中七个稳健性元程序（MP1-MP7）具有不同的生物学意义和空间分布。MP3和MP4与偏向细胞毒性或衰竭状态的不同CD8 T细胞密切相关，而MP7以恶性程度最高为特征，其周围存在免疫锁定微环境，并在空间上与肌成纤维细胞（myCAFs）相关。值得注意的是，我们澄清了MP7和myCAFs之间的相互作用，其中MP7诱导成纤维细胞的趋化迁移并通过GDF15/TGFBR2促进其向myCAFs的转化，反过来，myCAFs衍生的RSPO3上调EGR1以促进GC细胞和人类PDOs向MP7的转化。最终，myCAFs在MP7周围的积累导致CD8 T细胞的浸润减少，导致免疫剥夺微环境和免疫治疗效果降低。此外，基于MP7 GC细胞的基因表达特征，我们预测了特异性药物，并验证了在相同浓度下Taselisib和Lapatinib对MP7 GC细胞的抑制作用比常规药物更强。综上所述，这些结果加深了对胃癌异质性的理解，并为在胃癌治疗中靶向MP7胃癌细胞及其与myCAFs相互作用环的新治疗策略铺平了道路。在胃癌中发现了7个强大的meta-program （MP1-MP7）。MP7与胃癌患者的转移和生存不良密切相关。MP7通过GDF15/TGFBR2促进成纤维细胞转化为myCAFs，形成免疫锁定微环境。MyCAFs通过RSPO3/EGR1途径诱导MP7转化，促进胃癌细胞迁移。Taselisib和Lapatinib是MP7 GC细胞的有效抑制剂。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.