Spatially Resolved Tumor Ecosystems and Cell States in Gastric Adenocarcinoma Progression and Evolution

IF 29.7 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2025-01-08 DOI:10.1158/2159-8290.cd-24-0605

Haoran Ma, Supriya Srivastava, Shamaine Wei Ting Ho, Chang Xu, Benedict Shi Xiang Lian, Xuewen Ong, Su Ting Tay, Taotao Sheng, Huey Yew Jeffrey Lum, Siti Aishah Binte Abdul Ghani, Yunqiang Chu, Kie Kyon Huang, Yeek Teck Goh, Minghui Lee, Takeshi Hagihara, Clara Shi Ya Ng, Angie Lay Keng Tan, Yanrong Zhang, Zichen Ding, Feng Zhu, Michelle Shu Wen Ng, Craig Ryan Cecil Joseph, Hui Chen, Zhen Li, Joseph J. Zhao, Sun Young Rha, Ming Teh, Joe Yeong, Wei Peng Yong, Jimmy Bok-Yan So, Raghav Sundar, Patrick Tan

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引用次数: 0

Abstract

Gastric cancer (GC) is a major cause of global cancer mortality with high levels of heterogeneity. To explore geospatial interactions in tumor ecosystems, we integrated 2,138 spatial transcriptomic regions-of-interest (ROIs) with 152,423 single-cell expression profiles across 226 GC samples from 121 patients. We observed pervasive expression-based intratumor heterogeneity, recapitulating tumor progression through spatially localized and functionally ordered subgroups associated with specific immune microenvironments, checkpoint profiles, and genetic drivers such as SOX9. Evolutionary phylogenetic analysis revealed two different evolutionary trajectories (branched evolution and internal diaspora evolution) associated with distinct molecular subtypes, clinical prognoses, and stromal neighborhoods including VWF+ ACKR1+ endothelial cells. Spatial analysis of tumor-stromal interfaces across multiple GCs highlighted new ecosystem states not attributable to mere tumor/stroma admixture, landmarked by increased GREM1 expression. Our results provide insights into how the cellular ecosystems of individual GCs are sculpted by tumor intrinsic and extrinsic selective pressures, culminating in individualized patient-specific cancer cartographies.

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空间分解肿瘤生态系统和细胞状态在胃腺癌的进展和进化

胃癌（GC）是全球癌症死亡率的主要原因，具有高度的异质性。为了探索肿瘤生态系统中的地理空间相互作用，我们整合了来自121名患者的226个GC样本中的2138个空间转录组感兴趣区域（roi）和152423个单细胞表达谱。我们观察到普遍的基于表达的肿瘤内异质性，通过与特定免疫微环境、检查点谱和遗传驱动因素（如SOX9）相关的空间定位和功能有序亚群概括肿瘤进展。进化系统发育分析揭示了两种不同的进化轨迹（分支进化和内部散居进化）与不同的分子亚型、临床预后和基质邻域（包括VWF+ ACKR1+内皮细胞）相关。跨多个gc的肿瘤-基质界面的空间分析突出了新的生态系统状态，而不仅仅是由于肿瘤/基质的混合，以GREM1表达增加为标志。我们的研究结果揭示了个体胃癌的细胞生态系统是如何被肿瘤的内在和外在选择压力塑造的，最终形成了个性化的患者特异性癌症制图。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.