Cell Reports (Nov 2024)
A platform of functional studies of ESCC-associated gene mutations identifies the roles of TGFBR2 in ESCC progression and metastasis
- Jian Wang,
- Jiajia Du,
- Xiangmeng Luo,
- Linjie Guo,
- Yixin Liu,
- Jianfeng Zhou,
- Yang Zou,
- Zhenghao Lu,
- Xiangyu Pan,
- Xuelan Chen,
- Ailing Zhong,
- Xudong Wan,
- Lu Wang,
- Hongyu Liu,
- Siqi Dai,
- Shiyu Zhang,
- Xingyu Xiong,
- Ping Tan,
- Manli Wang,
- Baohong Wu,
- Qi Zhang,
- Yingjie Wang,
- Mengsha Zhang,
- Runda Lu,
- Huahang Lin,
- Yuan Li,
- Yaxin Li,
- Zongkai Han,
- Longqi Chen,
- Bing Hu,
- Yu Liu,
- Feifei Na,
- Chong Chen
Affiliations
- Jian Wang
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Jiajia Du
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Xiangmeng Luo
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Linjie Guo
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Yixin Liu
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Jianfeng Zhou
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Yang Zou
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Zhenghao Lu
- Chengdu OrganoidMed Medical Laboratory, West China Health Valley, Chengdu, Sichuan 610041, China
- Xiangyu Pan
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Xuelan Chen
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Ailing Zhong
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Xudong Wan
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Lu Wang
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Hongyu Liu
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Siqi Dai
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Shiyu Zhang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Xingyu Xiong
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Ping Tan
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Manli Wang
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Baohong Wu
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Qi Zhang
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Yingjie Wang
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Mengsha Zhang
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Runda Lu
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Huahang Lin
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Yuan Li
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Yaxin Li
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Zongkai Han
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Longqi Chen
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Corresponding author
- Bing Hu
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Corresponding author
- Yu Liu
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Corresponding author
- Feifei Na
- Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Corresponding author
- Chong Chen
- Department of Gastroenterology, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, No387-201 Hemin st., Chengdu, Sichuan 610212, China; Children's Medicine Key Laboratory of Sichuan Province, Sichuan 610041, China; Corresponding author
- Journal volume & issue
-
Vol. 43,
no. 11
p. 114952
Abstract
Summary: 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.
