A platform of functional studies of ESCC-associated gene mutations identifies the roles of TGFBR2 in ESCC progression and metastasis
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.
Authors
- Xingyu Xiong (ORCID: https://orcid.org/0009-0002-7562-1066)
- Yixin Liu (ORCID: https://orcid.org/0000-0002-1999-3175)
- Siqi Dai (ORCID: https://orcid.org/0000-0001-9313-1357)
- Xudong Wan
- Huahang Lin
- Xiangyu Pan (ORCID: https://orcid.org/0000-0002-2537-6616)
- Manli Wang (ORCID: https://orcid.org/0000-0001-8701-3530)
- Ping Tan (ORCID: https://orcid.org/0000-0002-7445-3577)
- Mengsha Zhang
- Zhenghao Lu
- Longqi Chen (ORCID: https://orcid.org/0000-0002-5036-5345)
- Feifei Na (ORCID: https://orcid.org/0000-0001-9364-1568)
- Zongkai Han
- Baohong Wu
- Chong Chen (ORCID: https://orcid.org/0000-0002-6787-0495)
- Yingjie Wang (ORCID: https://orcid.org/0000-0003-0920-9305)
- Qi Zhang (ORCID: https://orcid.org/0000-0001-9916-8919)
- Lu Wang (ORCID: https://orcid.org/0000-0003-2617-655X)
- Jian Wang (ORCID: https://orcid.org/0000-0002-9482-5227)
- Yaxin Li (ORCID: https://orcid.org/0000-0003-3205-3740)
- Shiyu Zhang (ORCID: https://orcid.org/0000-0003-0923-800X)
- Yuan Li (ORCID: https://orcid.org/0000-0002-5969-708X)
- Xiaoling Luo (ORCID: https://orcid.org/0009-0004-9640-7899)
- Bing Hu
- Jianfeng Zhou (ORCID: https://orcid.org/0000-0003-4413-6375)
- Ailing Zhong (ORCID: https://orcid.org/0000-0002-8044-1222)
- Xuelan Chen
- Runda Lu
- Jiajia Du (ORCID: https://orcid.org/0009-0002-5235-7629)
- Linjie Guo
- Yu Liu (ORCID: https://orcid.org/0000-0003-1337-2527)
- Hongyu Liu (ORCID: https://orcid.org/0000-0003-0383-8725)
Institutions
- Sichuan University (CN)
- West China Medical Center of Sichuan University (CN)
- West China Hospital of Sichuan University (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-11-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114952
- Citations
- 6
- Primary Topic
- TGF-β signaling in diseases
- Type
- article
- Field-Weighted Citation Impact
- 1.17