Single-cell pharmacogenomic landscapes of epigenetic therapy revealed by gastric cancer Perturb-seq

Gene expression signatures (“molecular phenotypes”) are extensively utilized in cancer research. To study how gastric cancer molecular phenotypes are regulated by cell-intrinsic genetic alterations interacting with cell-extrinsic therapeutic pressures, we performed direct capture Perturb-seq to interrogate >200 gastric cancer-related genes against 4 distinct epigenetic therapies in normal gastric and gastric cancer lines. We identify 17.7 million pharmocogenomic expression interactions in 625,866 cells representing baseline and post-therapeutic molecular phenotypes. This single-cell pharmacogenomic compendium confirms previously known gene-driven molecular phenotypes, elucidating both poorly characterized genes and gene dosage-molecular phenotype relationships. Molecular phenotypes in post-therapeutic surviving cells capture perturbation-associated pathways associated with drug resistance (epithelial–mesenchymal transition, cell cycle alterations, metabolic reprogramming). Mapping of in vitro molecular phenotypes to primary human gastric cancers uncovers prognostic and spatial variability. Comparative analysis of gene perturbations across therapies and lines reveals both conserved and context-specific molecular alterations. Our results provide a community resource for exploring how Perturb-seq molecular phenotypes are influenced by context dependencies across different drug exposures and cell line backgrounds. Gene expression signatures are widely used in cancer research. This study applies single-cell Perturb-seq to gastric cancer models under epigenetic therapies and reveals gene- and treatment-specific molecular phenotypes and drug-response pathways that have prognostic significance in primary tumours.

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Journal
Nature Communications
Published
2026-11-02
DOI
https://doi.org/10.1038/s41467-026-79125-0
Primary Topic
Single-cell and spatial transcriptomics
Type
article
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article

Single-cell pharmacogenomic landscapes of epigenetic therapy revealed by gastric cancer Perturb-seq

Xuewen Ong, Patrick B. O. Tan, Wei Peng Yong, David R. Powell et al.
1 links
Nature Communications
Single-cell and spatial transcriptomics
article

Single-cell pharmacogenomic landscapes of epigenetic therapy revealed by gastric cancer Perturb-seq

Xuewen Ong, Patrick B. O. Tan, Wei Peng Yong, David R. Powell, Anand Devaprasath D. Jeyasekharan, Taotao Sheng, Kie Kyon Huang, Joseph Rosenbluh, Shamaine Wei Ting Ho, Raghav Sundar, Siti Aishah Binte Abdul Ghani, Feng Zhu, Jimmy Bok Yan So, Hassan Ashktorab, Haoran Ma, Chang Xu, Su Ting Tay, Shang Li, Supriya Srivastava, Laura Perlaza-Jiménez, Ming Teh, Alfred Sze‐Lok Cheng, Angie Lay Keng Tan, Ming Hui Lee, Zhi Xuan Ong, Shen Kiat Lim
article en

Abstract

Gene expression signatures (“molecular phenotypes”) are extensively utilized in cancer research. To study how gastric cancer molecular phenotypes are regulated by cell-intrinsic genetic alterations interacting with cell-extrinsic therapeutic pressures, we performed direct capture Perturb-seq to interrogate >200 gastric cancer-related genes against 4 distinct epigenetic therapies in normal gastric and gastric cancer lines. We identify 17.7 million pharmocogenomic expression interactions in 625,866 cells representing baseline and post-therapeutic molecular phenotypes. This single-cell pharmacogenomic compendium confirms previously known gene-driven molecular phenotypes, elucidating both poorly characterized genes and gene dosage-molecular phenotype relationships. Molecular phenotypes in post-therapeutic surviving cells capture perturbation-associated pathways associated with drug resistance (epithelial–mesenchymal transition, cell cycle alterations, metabolic reprogramming). Mapping of in vitro molecular phenotypes to primary human gastric cancers uncovers prognostic and spatial variability. Comparative analysis of gene perturbations across therapies and lines reveals both conserved and context-specific molecular alterations. Our results provide a community resource for exploring how Perturb-seq molecular phenotypes are influenced by context dependencies across different drug exposures and cell line backgrounds. Gene expression signatures are widely used in cancer research. This study applies single-cell Perturb-seq to gastric cancer models under epigenetic therapies and reveals gene- and treatment-specific molecular phenotypes and drug-response pathways that have prognostic significance in primary tumours.

Nature Communications
Agency for Science, Technology and Research (SG), Howard University (US), SingHealth (SG), National University of Singapore (SG), Chinese University of Hong Kong (HK), SingHealth Duke-NUS Academic Medical Centre (SG), National University Cancer Institute, Singapore (SG), Duke-NUS Medical School (SG), National University Hospital (SG), National Heart Centre Singapore (SG), National University Health System (SG), Cancer Science Institute of Singapore (SG), Monash University (AU), Genome Institute of Singapore (SG)
Good health and well-being
Openalex Percentile: Top 100%
Single-cell and spatial transcriptomics
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