%0 Journal Article
%T Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1.
%A Zhong Q
%A Wang HG
%A Yang JH
%A Tu RH
%A Li AY
%A Zeng GR
%A Zheng QL
%A Yu Liu Z
%A Shang-Guan ZX
%A Bo Huang X
%A Huang Q
%A Li YF
%A Zheng HL
%A Lin GT
%A Huang ZN
%A Xu KX
%A Qiu WW
%A Jiang MC
%A Zhao YJ
%A Lin JX
%A Huang ZH
%A Huang JM
%A Li P
%A Xie JW
%A Zheng CH
%A Chen QY
%A Huang CM
%J Adv Sci (Weinh)
%V 10
%N 32
%D 2023 11 12
%M 37824217
%F 17.521
%R 10.1002/advs.202301977
%X 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.