Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1
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 sam...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-11-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202301977 |
| _version_ | 1797627766086041600 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Qing Zhong |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T10:29:06Z |
| format | Article |
| id | doaj.art-d5c450371d7249f382f7578885a3dc87 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-11T10:29:06Z |
| publishDate | 2023-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-d5c450371d7249f382f7578885a3dc872023-11-15T05:46:36ZengWileyAdvanced Science2198-38442023-11-011032n/an/a10.1002/advs.202301977Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1Qing Zhong0Hua‐Gen Wang1Ji‐Hong Yang2Ru‐Hong Tu3An‐Yao Li4Gui‐Rong Zeng5Qiao‐Ling Zheng6Zhi‐ Yu Liu7Zhi‐Xin Shang‐Guan8Xiao‐ Bo Huang9Qiang Huang10Yi‐Fan Li11Hua‐Long Zheng12Guang‐Tan Lin13Ze‐Ning Huang14Kai‐Xiang Xu15Wen‐Wu Qiu16Mei‐Chen Jiang17Ya‐Jun Zhao18Jian‐Xian Lin19Zhi‐Hong Huang20Jing‐Min Huang21Ping Li22Jian‐Wei Xie23Chao‐Hui Zheng24Qi‐Yue Chen25Chang‐Ming Huang26Department of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaBoYu Intelligent Health Innovation Laboratory Hangzhou 311100 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaCollege of Pharmaceutical Sciences Zhejiang University Hangzhou 310058 P. R. ChinaDepartment of Pathology Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDiagnostic Pathology Center Fujian Medical University Fuzhou 350001 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDiagnostic Pathology Center Fujian Medical University Fuzhou 350001 P. R. ChinaDepartment 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. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaPublic Technology Service Center Fujian Medical University Fuzhou 350122 P. R. ChinaDepartment of General Surgery Qinghai Provincial People's Hospital Xining 810000 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaDepartment of Gastric Surgery Fujian Medical University Union Hospital Fuzhou 350001 P. R. ChinaAbstract 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.https://doi.org/10.1002/advs.202301977ATOH1GAS1gastric adenocarcinomamouse modelstemness |
| spellingShingle | 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 Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1 Advanced Science ATOH1 GAS1 gastric adenocarcinoma mouse model stemness |
| title | Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1 |
| title_full | Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1 |
| title_fullStr | Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1 |
| title_full_unstemmed | Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1 |
| title_short | Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1 |
| title_sort | loss of atoh1 in pit cell drives stemness and progression of gastric adenocarcinoma by activating akt mtor signaling through gas1 |
| topic | ATOH1 GAS1 gastric adenocarcinoma mouse model stemness |
| url | https://doi.org/10.1002/advs.202301977 |
| work_keys_str_mv | AT qingzhong lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT huagenwang lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT jihongyang lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT ruhongtu lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT anyaoli lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT guirongzeng lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT qiaolingzheng lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT zhiyuliu lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT zhixinshangguan lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT xiaobohuang lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT qianghuang lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT yifanli lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT hualongzheng lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT guangtanlin lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT zeninghuang lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT kaixiangxu lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT wenwuqiu lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT meichenjiang lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT yajunzhao lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT jianxianlin lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT zhihonghuang lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT jingminhuang lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT pingli lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT jianweixie lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT chaohuizheng lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT qiyuechen lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 AT changminghuang lossofatoh1inpitcelldrivesstemnessandprogressionofgastricadenocarcinomabyactivatingaktmtorsignalingthroughgas1 |