<br>凹细胞中 ATOH1 的缺失通过 GAS1 激活 AKT/mTOR 信号来驱动胃腺癌的干细胞性和进展,Advanced Science

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凹细胞中 ATOH1 的缺失通过 GAS1 激活 AKT/mTOR 信号来驱动胃腺癌的干细胞性和进展
Advanced Science ( IF 14.3 ) Pub Date : 2023-10-12 , DOI: 10.1002/advs.202301977
Qing Zhong _{1,

2,

3} , Hua-Gen Wang _{1,

2,

3} , Ji-Hong Yang ₄ , Ru-Hong Tu _{1,

2,

3} , An-Yao Li ₅ , Gui-Rong Zeng ₆ , Qiao-Ling Zheng ₇ , Zhi- Yu Liu _{1,

2,

3} , Zhi-Xin Shang-Guan _{1,

2,

3} , Xiao- Bo Huang _{1,

2,

3} , Qiang Huang _{1,

2,

3} , Yi-Fan Li _{1,

2,

3} , Hua-Long Zheng _{1,

2,

3} , Guang-Tan Lin _{1,

2,

3} , Ze-Ning Huang _{1,

2,

3} , Kai-Xiang Xu _{1,

2,

3} , Wen-Wu Qiu _{1,

2,

3} , Mei-Chen Jiang ₇ , Ya-Jun Zhao ₈ , Jian-Xian Lin _{1,

2,

3} , Zhi-Hong Huang ₉ , Jing-Min Huang ₁₀ , Ping Li _{1,

2,

3} , Jian-Wei Xie _{1,

2,

3} , Chao-Hui Zheng _{1,

2,

3} , Qi-Yue Chen _{1,

2,

3} , Chang-Ming Huang _{1,

2,

3}

Affiliation

Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, P. R. China.
Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, P. R. China.
Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350122, P. R. China.
BoYu Intelligent Health Innovation Laboratory, Hangzhou, 311100, P. R. China.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China.
Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, 350001, P. R. China.
Diagnostic Pathology Center, Fujian Medical University, Fuzhou, 350001, P. R. China.
Department of Gastrointestinal Surgery, The First Affiliated Hospital of the University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, P. R. China.
Public Technology Service Center, Fujian Medical University, Fuzhou, 350122, P. R. China.
Department of General Surgery, Qinghai Provincial People's Hospital, Xining, 810000, P. R. China.

胃癌干细胞（GCSC）是自我更新的肿瘤细胞，控制胃腺癌（GAC）的化疗耐药性，但其调节机制仍然难以捉摸。本研究旨在阐明ATOH1在维持 GCSC 中的作用。临床前模型和 GAC 样本分析表明ATOH1缺陷与 GAC 预后不良和化疗耐药相关。 ScRNA-seq 显示，与癌旁样本相比，GAC 的凹陷细胞中ATOH1表达下调。谱系追踪表明Atoh1缺失强烈赋予凹坑细胞干性。 ATOH1耗竭显着加速Tff1-CreERT2 中的癌症干性和化疗耐药性； Rosa26 ^Tdtomato和Tff1-CreERT2； APC^{液位/液位}； p53 ^fl/fl ( TcPP ) 小鼠模型和类器官。 ATOH1缺陷通过抑制GAS1启动子转录来下调生长停滞特异性蛋白 1 ( GAS1 )。 GAS1与RET形成复合物，抑制 Tyr1062 磷酸化，从而通过ATOH1缺陷激活RET / AKT / mTOR信号通路。将化疗与靶向AKT / mTOR信号传导的药物相结合可以克服ATOH1缺陷引起的化疗耐药。此外，已证实异常的DNA高甲基化会导致ATOH1缺陷。综上所述，结果表明ATOH1缺失通过 GAC 中的ATOH1 / GAS1 / RET / AKT / mTOR信号通路促进癌症干性，从而为ATOH1缺陷的 GAC 患者提供AKT / mTOR抑制剂的潜在治疗策略。

"点击查看英文标题和摘要"

Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1

Gastric cancer stem cells (GCSCs) are self-renewing tumor cells that govern chemoresistance in gastric adenocarcinoma (GAC), whereas their regulatory mechanisms remain elusive. Here, the study aims to elucidate the role of ATOH1 in the maintenance of GCSCs. The preclinical model and GAC sample analysis indicate that ATOH1 deficiency is correlated with poor GAC prognosis and chemoresistance. ScRNA-seq reveals that ATOH1 is downregulated in the pit cells of GAC compared with those in paracarcinoma samples. Lineage tracing reveals that Atoh1 deletion strongly confers pit cell stemness. ATOH1 depletion significantly accelerates cancer stemness and chemoresistance in Tff1-CreERT2; Rosa26^Tdtomato and Tff1-CreERT2; Apc^fl/fl; p53^fl/fl (TcPP) mouse models and organoids. ATOH1 deficiency downregulates growth arrest-specific protein 1 (GAS1) by suppressing GAS1 promoter transcription. GAS1 forms a complex with RET, which inhibits Tyr1062 phosphorylation, and consequently activates the RET/AKT/mTOR signaling pathway by ATOH1 deficiency. Combining chemotherapy with drugs targeting AKT/mTOR signaling can overcome ATOH1 deficiency-induced chemoresistance. Moreover, it is confirmed that abnormal DNA hypermethylation induces ATOH1 deficiency. Taken together, the results demonstrate that ATOH1 loss promotes cancer stemness through the ATOH1/GAS1/RET/AKT/mTOR signaling pathway in GAC, thus providing a potential therapeutic strategy for AKT/mTOR inhibitors in GAC patients with ATOH1 deficiency.

更新日期：2023-10-12

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