A Comprehensive Human Gastric Cancer Organoid Biobank Captures Tumor Subtype Heterogeneity and Enables Therapeutic Screening
Helen H N Yan, Hoi Cheong Siu, Simon Law, Siu Lun Ho, Sarah S K Yue, Wai Yin Tsui, Dessy Chan, April S Chan, Stephanie Ma, Ka On Lam, Sina Bartfeld, Alice H Y Man, Bernard C H Lee, Annie S Y Chan, Jason W H Wong, Priscilla S W Cheng, Anthony K W Chan, Jiangwen Zhang, Jue Shi, Xiaodan Fan, Dora L W Kwong, Tak W Mak, Siu Tsan Yuen, Hans Clevers, Suet Yi Leung, Helen H N Yan, Hoi Cheong Siu, Simon Law, Siu Lun Ho, Sarah S K Yue, Wai Yin Tsui, Dessy Chan, April S Chan, Stephanie Ma, Ka On Lam, Sina Bartfeld, Alice H Y Man, Bernard C H Lee, Annie S Y Chan, Jason W H Wong, Priscilla S W Cheng, Anthony K W Chan, Jiangwen Zhang, Jue Shi, Xiaodan Fan, Dora L W Kwong, Tak W Mak, Siu Tsan Yuen, Hans Clevers, Suet Yi Leung
Abstract
Gastric cancer displays marked molecular heterogeneity with aggressive behavior and treatment resistance. Therefore, good in vitro models that encompass unique subtypes are urgently needed for precision medicine development. Here, we have established a primary gastric cancer organoid (GCO) biobank that comprises normal, dysplastic, cancer, and lymph node metastases (n = 63) from 34 patients, including detailed whole-exome and transcriptome analysis. The cohort encompasses most known molecular subtypes (including EBV, MSI, intestinal/CIN, and diffuse/GS, with CLDN18-ARHGAP6 or CTNND1-ARHGAP26 fusions or RHOA mutations), capturing regional heterogeneity and subclonal architecture, while their morphology, transcriptome, and genomic profiles remain closely similar to in vivo tumors, even after long-term culture. Large-scale drug screening revealed sensitivity to unexpected drugs that were recently approved or in clinical trials, including Napabucasin, Abemaciclib, and the ATR inhibitor VE-822. Overall, this new GCO biobank, with linked genomic data, provides a useful resource for studying both cancer cell biology and precision cancer therapy.
Keywords: ARHGAP fusions; EBV genome; RHOA mutations; biobank; drug screening; gastric cancer; heterogeneity; organoid culture; transcriptome sequencing; whole-exome sequencing.
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Source: PubMed