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

Zhongguang Luo; Bangting Wang; Feifei Luo; Yumeng Guo; Ning Jiang; Jinsong Wei; Xin Wang; Yujen Tseng; Jian Chen; Bing Zhao; Jie Liu

doi:10.1186/s12916-023-03034-y

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

BMC Med. 2023 Sep 4;21(1):336. doi: 10.1186/s12916-023-03034-y.

Authors

Zhongguang Luo^#¹, Bangting Wang^#¹, Feifei Luo^#¹, Yumeng Guo^#¹, Ning Jiang², Jinsong Wei², Xin Wang², Yujen Tseng¹, Jian Chen¹, Bing Zhao^{3

4}, Jie Liu^{5

6}

Affiliations

¹ Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China.
² State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
³ State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China. bingzhao@fudan.edu.cn.
⁴ Institute of Organoid Technology, Kunming Medical University, Kunming, 650500, China. bingzhao@fudan.edu.cn.
⁵ Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China. jieliu@fudan.edu.cn.
⁶ Institute of Biomedical Sciences and Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. jieliu@fudan.edu.cn.

^# Contributed equally.

Abstract

Background: Colorectal 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.

Methods: We 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.

Results: We 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.

Conclusions: This 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.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenoma* / drug therapy
Adenoma* / genetics
Biological Specimen Banks
Colorectal Neoplasms* / drug therapy
Drug Evaluation, Preclinical
Humans
Metformin*
Organoids

Substances

Metformin