Establishment of a large-scale patient-derived high-risk colorectal adenoma organoid biobank for high-throughput and high-content drug screening

BMC Medicine

Research Article

Bangting Wang¹  Yumeng Guo¹  Jian Chen¹  Zhongguang Luo¹  Yujen Tseng¹  Feifei Luo¹  Jie Liu²  Jinsong Wei³  Ning Jiang³  Xin Wang³  Bing Zhao⁴ 

[1] Department of Digestive Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China;Department of Digestive Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China;Institute of Biomedical Sciences and Department of Immunology, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China;State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, 200438, Shanghai, China;State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, 200438, Shanghai, China;Institute of Organoid Technology, Kunming Medical University, 650500, Kunming, China;

关键词: Patient-derived high-risk colorectal adenoma organoid (HRCA-PDO);    Biobank;    High throughput drug screening;    Stemness;    Metformin;   

DOI  :  10.1186/s12916-023-03034-y

 received in 2022-11-18, accepted in 2023-08-15,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundColorectal adenoma (CA), especially high-risk CA (HRCA), is a precancerous lesion with high prevalence and recurrence rate and accounts for about 90% incidence of sporadic colorectal cancer cases worldwide. Currently, recurrent CA can only be treated with repeated invasive polypectomies, while safe and promising pharmaceutical invention strategies are still missing due to the lack of reliable in vitro model for CA-related drug screening.MethodsWe have established a large-scale patient-derived high-risk colorectal adenoma organoid (HRCA-PDO) biobank containing 37 PDO lines derived from 33 patients and then conducted a series of high-throughput and high-content HRCA drug screening.ResultsWe established the primary culture system with the non-WNT3a medium which highly improved the purity while maintained the viability of HRCA-PDOs. We also proved that the HRCA-PDOs replicated the histological features, cellular diversity, genetic mutations, and molecular characteristics of the primary adenomas. Especially, we identified the dysregulated stem genes including LGR5, c-Myc, and OLFM4 as the markers of adenoma, which are well preserved in HRCA-PDOs. Based on the HRCA-PDO biobank, a customized 139 compound library was applied for drug screening. Four drugs including metformin, BMS754807, panobinostat and AT9283 were screened out as potential hits with generally consistent inhibitory efficacy on HRCA-PDOs. As a representative, metformin was discovered to hinder HRCA-PDO growth in vitro and in vivo by restricting the stemness maintenance.ConclusionsThis study established a promising HRCA-PDO biobank and conducted the first high-throughput and high-content HRCA drug screening in order to shed light on the prevention of colorectal cancer.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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