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

Autor: Zhong Q; 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., Wang HG; 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., Yang JH; BoYu Intelligent Health Innovation Laboratory, Hangzhou, 311100, P. R. China., Tu RH; 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., Li AY; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China., Zeng GR; Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, 350001, P. R. China., Zheng QL; Diagnostic Pathology Center, Fujian Medical University, Fuzhou, 350001, P. R. China., Yu Liu Z; 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., Shang-Guan ZX; 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., Bo Huang X; 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., Huang Q; 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., Li YF; 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., Zheng HL; 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., Lin GT; 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., Huang ZN; 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., Xu KX; 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., Qiu WW; 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., Jiang MC; Diagnostic Pathology Center, Fujian Medical University, Fuzhou, 350001, P. R. China., Zhao YJ; 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., Lin JX; 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., Huang ZH; Public Technology Service Center, Fujian Medical University, Fuzhou, 350122, P. R. China., Huang JM; Department of General Surgery, Qinghai Provincial People's Hospital, Xining, 810000, P. R. China., Li P; 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., Xie JW; 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., Zheng CH; 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., Chen QY; 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., Huang CM; 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.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2023 Nov; Vol. 10 (32), pp. e2301977. Date of Electronic Publication: 2023 Oct 12.
DOI: 10.1002/advs.202301977
Abstrakt: 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.
(© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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