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

• DOI: 10.1002/advs.202301977
• Publication Date: 2023-10-12T16:13:28Z
• Authors: Qing Zhong; Hua‐Gen Wang; Ji‐Hong Yang; Ru‐Hong Tu; An‐Yao Li; Gui‐Rong Zeng; Qiao‐Ling Zheng; Zhi‐ Yu Liu; Zhi‐Xin Shang‐Guan; Xiao‐ Bo Huang; Qiang Huang; Yi‐Fan Li; Hua‐Long Zheng; Guang‐Tan Lin; Ze‐Ning Huang; Kai‐Xiang Xu; Wen‐Wu Qiu; Mei‐Chen Jiang; Ya‐Jun Zhao; Jian‐Xian Lin; Zhi‐Hong Huang; Jing‐Min Huang; Ping Li; Jian‐Wei Xie; Chao‐Hui Zheng; Qi‐Yue Chen; Chang‐Ming Huang
• Keywords: stemness; GAS1; ATOH1; mouse model; Science; Q; gastric adenocarcinoma; Research Articles; 3. Good health

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