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

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; Ming‐Hui Lee; Takeshi Hagihara; Clara Shi Ya Ng; Angie Lay Keng Tan; Yanrong Zhang; Zichen Ding; Feng Zhu; Michelle Shu Wen Ng; Craig Ryan Joseph; Hui Chen; Zhen Li; Joseph Jonathan Zhao; Sun Young Rha; Ming Teh; Joe Poh-Sheng Yeong; Wei Peng Yong; Jimmy Bok Yan So

doi:10.1158/2159-8290.cd-24-0605

Cancer BiologyCancer DiscoveryJan 8, 2025

Peer-reviewed journal article

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

Haoran Ma iD, Supriya Srivastava iD, Shamaine Wei Ting Ho iD, Chang Xu iD, Benedict Shi Xiang Lian iD, Xuewen Ong iD, Su Ting Tay iD, Taotao Sheng iD, Huey Yew Jeffrey Lum iD, Siti Aishah Binte Abdul Ghani iD, Yunqiang Chu iD, Kie Kyon Huang iD, Yeek Teck Goh iD, Ming‐Hui Lee iD, Takeshi Hagihara iD, Clara Shi Ya Ng iD, Angie Lay Keng Tan iD, Yanrong Zhang iD, Zichen Ding iD, Feng Zhu iD, Michelle Shu Wen Ng iD, Craig Ryan Joseph iD, Hui Chen iD, Zhen Li iD, Joseph Jonathan Zhao iD, , Patrick B. O. Tan iD

Abstract

Gastric cancer (GC) is a major cause of global cancer mortality with high heterogeneity levels. To explore geospatial interactions in tumor ecosystems, we integrated 1,563 spatial transcriptomic regions-of-interest (ROIs) with 152,423 single-cell expression profiles across 130 GC samples from 70 patients. We observed pervasive expression-based intratumor heterogeneity, recapitulating tumor progression through spatially localized and functionally ordered subgroups with specific immune microenvironments and immune checkpoint profiles. Evolutionary phylogenetic analysis revealed two different evolutionary trajectories (branched evolution and diaspora evolution) associated with distinct molecular subtypes, clinical prognoses, stromal neighborhoods including VWF+ ACKR1+ endothelial cells, and genetic drivers such as SOX9. 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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