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A platform of functional studies of ESCC-associated gene mutations identifies the roles of TGFBR2 in ESCC progression and metastasis

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资源类型：
Pubmed体系：
作者：
Wang Jian[1] * ; Du Jiajia[1] * ; Luo Xiangmeng[1] * ; Guo Linjie[1] * ; Liu Yixin[2] * ; Zhou Jianfeng[2] ; Zou Yang[1] ; Lu Zhenghao[3] ; Pan Xiangyu[1] ; Chen Xuelan[1] ; Zhong Ailing[1] ; Wan Xudong[1] ; Wang Lu[1] ; Liu Hongyu[1] ; Dai Siqi[1] ; Zhang Shiyu[4] ; Xiong Xingyu[4] ; Tan Ping[4] ; Wang Manli[1] ; Wu Baohong[1] ; Zhang Qi[1] ; Wang Yingjie[1] ; Zhang Mengsha[1] ; Lu Runda[2] ; Lin Huahang[2] ; Li Yuan[1] ; Li Yaxin[1] ; Han Zongkai[1] ; Chen Longqi[2] ; Hu Bing[1] ; Liu Yu[1] ; Na Feifei[6] ; Chen Chong[1,5,7,9] ;
机构： [1]Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China [2]Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China [3]Chengdu OrganoidMed Medical Laboratory, West China Health Valley, Chengdu, Sichuan 610041, China [4]Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China [5]Frontiers Medical Center, Tianfu Jincheng Laboratory, No387-201 Hemin st., Chengdu, Sichuan 610212, China [6]Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China [7]Children’s Medicine Key Laboratory of Sichuan Province, Sichuan 610041, China
出处：
DOI： 10.1016/j.celrep.2024.114952

摘要：
Genomics studies have detected numerous genetic alterations in esophageal squamous cell carcinoma (ESCC). However, the functions of these mutations largely remain elusive, partially due to a lack of feasible animal models. Here, we report a convenient platform with CRISPR-Cas9-mediated introduction of genetic alterations and orthotopic transplantation to generate a series of primary ESCC models in mice. With this platform, we validate multiple frequently mutated genes, including EP300, FAT1/2/4, KMT2D, NOTCH2, and TGFBR2, as tumor-suppressor genes in ESCC. Among them, TGFBR2 loss dramatically promotes tumorigenesis and multi-organ metastasis. Paradoxically, TGFBR2 deficiency leads to Smad3 activation, and disruption of Smad3 partially restrains the progression of Tgfbr2-mutated tumors. Drug screening with tumor organoids identifies that pinaverium bromide represses Smad3 activity and restrains Tgfbr2-deficient ESCC. Our studies provide a highly efficient platform to investigate the in vivo functions of ESCC-associated mutations and develop potential treatments for this miserable malignancy.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

基金：
We thank the Chen-Liu lab members for discussions and technical support; the Department of Gastroenterology and the Department of Thoracic Surgery for their clinical resources; Professor Deying Kang of statistics (West China Hospital, Sichuan University, China) for the constructive suggestions on the clinical survival analysis; the Core Facilities of West China Hospital, Sichuan University, and the Chengdu Organoid Med Medical Laboratory for technical support; and Fangfang Wang (Institute of Hematology, West China Hospital) and Shasha Du for the graphical abstract artwork. This study was supported by the National Natural Science Foundation of China (82330087, T2221004, 82130007, 82170171, 82472783, 82000514, 82170675, and 82303317); the Frontiers Medical Center, Tianfu Jincheng Laboratory Foundation (TFJC2023010004); the 1.3.5. Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYJC21003, ZYGD22012, and ZYJC21011); the Sichuan Science and Technology Program (2023ZYD0057 and 2023NSFSC1904); the National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (Z2024JC001); the Basic Research Projects of Qinghai Provincial Department of Science and Technology (2023-ZJ-791); the China Postdoctoral Science Foundation (2023M732434 and 2023M732457); the Sichuan Province Innovative Talent Funding Project for Postdoctoral Fellows; and the Postdoctoral Fellowship Program of CPSF (GZB20230466).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2024]版：
无
最新[2023]版：
大类 | 1 区 生物学
小类 | 2 区 细胞生物学
第一作者：
第一作者机构： [1]Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
共同第一作者：
通讯作者：
通讯机构： [1]Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China [5]Frontiers Medical Center, Tianfu Jincheng Laboratory, No387-201 Hemin st., Chengdu, Sichuan 610212, China [7]Children’s Medicine Key Laboratory of Sichuan Province, Sichuan 610041, China
推荐引用方式(GB/T 7714)：
Wang Jian,Du Jiajia,Luo Xiangmeng,et al.A platform of functional studies of ESCC-associated gene mutations identifies the roles of TGFBR2 in ESCC progression and metastasis[J].Cell Reports.2024,43(11):114952.doi:10.1016/j.celrep.2024.114952.
APA：
Wang Jian,Du Jiajia,Luo Xiangmeng,Guo Linjie,Liu Yixin...&Chen Chong.(2024).A platform of functional studies of ESCC-associated gene mutations identifies the roles of TGFBR2 in ESCC progression and metastasis.Cell Reports,43,(11)
MLA：
Wang Jian,et al."A platform of functional studies of ESCC-associated gene mutations identifies the roles of TGFBR2 in ESCC progression and metastasis".Cell Reports 43..11(2024):114952

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