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Cell Stem Cell. 2018 Dec 6;23(6):882-897.e11. doi: 10.1016/j.stem.2018.09.016. Epub 2018 Oct 18.

A Comprehensive Human Gastric Cancer Organoid Biobank Captures Tumor Subtype Heterogeneity and Enables Therapeutic Screening.

Author information

1
Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. Electronic address: yanhelen@hku.hk.
2
Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
3
Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
4
School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
5
Department of Clinical Oncology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
6
Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, the Netherlands.
7
School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
8
Department of Biology and Department of Physics, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
9
Department of Statistics, Chinese University of Hong Kong, Shatin, Hong Kong.
10
Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
11
Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong; Department of Pathology, St. Paul's Hospital, No. 2, Eastern Hospital Road, Causeway Bay, Hong Kong.
12
Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, the Netherlands; Princess Maxima Center for Pediatric Oncology, 3584 CT Utrecht, the Netherlands.
13
Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong; The Jockey Club Centre for Clinical Innovation and Discovery, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong. Electronic address: suetyi@hku.hk.

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

PMID:
30344100
DOI:
10.1016/j.stem.2018.09.016
[Indexed for MEDLINE]

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