A 15-layer multi-omics analysis of gastric cancer ecotypes provides therapeutic insights

Yuefan Wang(Johns Hopkins University), Lindsey K. Olsen(Baylor College of Medicine), Fenglong Jiao(University of California, Irvine), Chenwei Wang(Baylor College of Medicine), Kevin X. Jiang(Dana-Farber Cancer Institute), Yongchao Dou(Baylor College of Medicine), Yingwei Hu(Johns Hopkins University), Liyuan Jiao(Johns Hopkins University), Wenrong Chen(Baylor College of Medicine), John M. Elizarraras(Baylor College of Medicine), Pratik Khare(Milligan College), Nengneng Yu(University of Maryland, College Park), Huili Zhu(The University of Texas MD Anderson Cancer Center), Lijun Chen(Johns Hopkins University), Tung-Shing M. Lih(Johns Hopkins University), Pınar Ö. Eser(Broad Institute), Fernanda Martins Rodrigues(Washington University in St. Louis), Zhiao Shi(Baylor College of Medicine), Cissy Zhang(Milligan College), Clinton Yu(University of California, Irvine), David I. Heiman(Broad Institute), Yuxing Liao(Baylor College of Medicine), Paul Shafer(Baylor College of Medicine), Seunghyuk Choi(Baylor College of Medicine), Jong Min Choi(Baylor College of Medicine), Sara R. Savage(Baylor College of Medicine), Eric J. Jaehnig(Baylor College of Medicine), Jonathan T. Lei(Baylor College of Medicine), Yanling Sun(Baylor College of Medicine), Chien‐Wei Peng(Washington University in St. Louis), Zhenyu Sun(Johns Hopkins University), Paul Morenkov(University of California, Irvine), Kevin Zhang(Johns Hopkins University), Yifat Geffen(Broad Institute), Julian Hess(Broad Institute), Chandan Kumar-Sinha(Michigan Center for Translational Pathology), DR Mani(Broad Institute), Li Ding(Washington University in St. Louis), Gad Getz(Center for Cancer Research), Qing Kay Li(Johns Hopkins University), Gilbert S. Omenn(University of Michigan), Anne Le(Milligan College), Galen Hostetter(Van Andel Institute), Chelsea J. Newton(Van Andel Institute), Shuang Cai(ICF International (United States)), Karen A. Ketchum(ICF International (United States)), Ana I. Robles(National Cancer Institute), Mehdi Mesri(National Cancer Institute), Parham Minoo(University of Calgary), M. Constanza Camargo(National Cancer Institute), Eunkyung An(National Cancer Institute), Ralph H. Hruban(Johns Hopkins University), Zaoxing Liu(University of Maryland, College Park), Mathangi Thiagarajan(Frederick National Laboratory for Cancer Research), Anders B. Dohlman(Dana-Farber Cancer Institute), Ramon U. Jin(Washington University in St. Louis), Lan Huang(University of California, Irvine), Daniel W. Chan(Johns Hopkins University), Hui Zhang(Johns Hopkins University), Bing Zhang(Baylor College of Medicine), Elleine Allapitan, Matthew Anderson, Oliver F. Bathe, Oleksandr Bolba, Brittney Borresen, Melissa Borucki, Steven A. Carr, Andra Ciocan, Reese Crispen, Diwakar Davar, Saravana Mohan Dhanasekaran, Marcin J. Domagalski, Nathan J. Edwards, Rafael Fonseca, Victoria Fulidou, Michael A. Gillette, Charles A. Goldthwaite, Vladislav S. Golubkov, Ramaswamy Govindan, Iga Kołodziejczak-Guglas, Toan Le, Tao Liu, Yin Lu, Avi Ma'ayan, Rashna Madan, Peter McGarvey, Dawid Murawa, Alexey I. Nesvizhskii, Kristen Nyce, Timothy M. Nywening, Akhilesh Pandey, Kristine Parikyan, Amanda G. Paulovich, Paul Piehowski, Alexander Pilozzi, Olga Potapova, Sergiy Revin, Michael Roehrl, Dan Rohrer, Rostyslav Semikov, Bohdana Shkurupii, Yvonne Shutack, Ratna R. Thangudu, Tsanko Tsankov, Jeffrey Tyner, Negin Vatanian, Miodrag Vucic, Pei Wang, Bart O. Williams, Maciej Wiznerowicz, Tongwu Zhang, Xu Zhang
Cell Reports Medicine
April 20, 2026
10.1016/j.xcrm.2026.102756
Cited by 0Open Access
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Abstract

Gastric cancer is marked by profound molecular and microenvironmental heterogeneity that limits therapeutic progress. Here, we present a 15-layer multi-omics atlas that integrates genomics, epigenomics, transcriptomics, proteomics, multiple post-translational modifications (PTMs), protein-protein interactions, metabolomics, and microbiome profiles from 159 primary gastric adenocarcinomas and 30 matched normal adjacent tissues. Using cell-state deconvolution, we define tumor ecotypes that refine genomic and histological subtypes by capturing distinct tumor microenvironment architectures linked to clinical outcomes and potential associations with immunotherapy response. Multi-omics integration prioritizes genomic and epigenomic aberrations and their associated vulnerabilities; defines ecotype-specific transcriptional programs, signaling pathways, PTMs, protein interaction networks, and metabolic regulation; and identifies microbiome features linked to ecotypes and resistance pathways. We further prioritize ecotype-, genomic subtype-, and cell type-specific targetable proteins using proteomic and PTM analyses within a tumor microenvironment context. This comprehensive atlas provides a systems-level blueprint for decoding gastric cancer heterogeneity and advancing precision oncology.

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