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

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

  • Adv Sci (Weinh). 2023 Oct 12:e2301977. 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
Affiliations

Affiliations

  • 1 Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, P. R. China.
  • 2 Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, P. R. China.
  • 3 Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350122, P. R. China.
  • 4 BoYu Intelligent Health Innovation Laboratory, Hangzhou, 311100, P. R. China.
  • 5 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China.
  • 6 Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, 350001, P. R. China.
  • 7 Diagnostic Pathology Center, Fujian Medical University, Fuzhou, 350001, P. R. China.
  • 8 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.
  • 9 Public Technology Service Center, Fujian Medical University, Fuzhou, 350122, P. R. China.
  • 10 Department of General Surgery, Qinghai Provincial People's Hospital, Xining, 810000, P. R. China.
PMID: 37824217 DOI: 10.1002/advs.202301977
Abstract

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; Rosa26Tdtomato and Tff1-CreERT2; APCfl/fl ; p53fl/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.

Keywords

ATOH1; GAS1; gastric adenocarcinoma; mouse model; stemness.

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