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

IF 7.5 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2024-11-10 DOI:10.1016/j.celrep.2024.114952

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

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Abstract

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.

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ESCC 相关基因突变的功能研究平台确定了 TGFBR2 在 ESCC 进展和转移中的作用。

基因组学研究在食管鳞状细胞癌（ESCC）中发现了许多基因突变。然而，这些基因突变的功能在很大程度上仍然难以捉摸，部分原因是缺乏可行的动物模型。在这里，我们报告了一个便捷的平台，通过 CRISPR-Cas9 介导的基因改变导入和正位移植，在小鼠体内生成一系列原发性 ESCC 模型。通过这一平台，我们验证了多个频繁突变的基因，包括EP300、FAT1/2/4、KMT2D、NOTCH2和TGFBR2，它们是ESCC的抑癌基因。其中，TGFBR2 基因缺失会显著促进肿瘤发生和多器官转移。矛盾的是，TGFBR2缺失会导致Smad3活化，而破坏Smad3可部分抑制Tgfbr2突变肿瘤的进展。利用肿瘤器官组织进行的药物筛选发现，匹维溴铵能抑制Smad3的活性，抑制Tgfbr2缺陷的ESCC。我们的研究为研究 ESCC 相关突变的体内功能和开发这种悲惨恶性肿瘤的潜在治疗方法提供了一个高效的平台。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.