SOX9 Modulates the Transformation of Gastric Stem Cells Through Biased Symmetric Cell Division

Qiyue Chen; Kai Weng; Mi Lin; Ming Jiang; Yinshan Fang; Sanny S W Chung; Xiaobo Huang; Qing Zhong; Zhiyu Liu; Zening Huang; Jianxian Lin; Ping Li; Wael El-Rifai; Alexander Zaika; Haiyan Li; Anil K Rustgi; Hiroshi Nakagawa; Julian A Abrams; Timothy C Wang; Chao Lu; Changming Huang; Jianwen Que

doi:10.1053/j.gastro.2023.01.037

SOX9 Modulates the Transformation of Gastric Stem Cells Through Biased Symmetric Cell Division

Gastroenterology. 2023 Jun;164(7):1119-1136.e12. doi: 10.1053/j.gastro.2023.01.037. Epub 2023 Feb 4.

Authors

Qiyue Chen¹, Kai Weng², Mi Lin¹, Ming Jiang³, Yinshan Fang⁴, Sanny S W Chung⁴, Xiaobo Huang², Qing Zhong², Zhiyu Liu², Zening Huang², Jianxian Lin², Ping Li², Wael El-Rifai⁵, Alexander Zaika⁵, Haiyan Li⁶, Anil K Rustgi⁷, Hiroshi Nakagawa⁷, Julian A Abrams⁷, Timothy C Wang⁷, Chao Lu⁸, Changming Huang⁹, Jianwen Que¹⁰

Affiliations

¹ Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China; Columbia Center for Human Development, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.
² Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, People's Republic of China.
³ National Clinical Research Center for Child Health of the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.
⁴ Columbia Center for Human Development, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.
⁵ Department of Surgery, University of Miami, Miami, Florida; Department of Veterans Affairs, Miami Healthcare System, Miami, Florida.
⁶ Department of Pathology & Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
⁷ Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.
⁸ Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York.
⁹ Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, People's Republic of China. Electronic address: hcmlr2002@163.com.
¹⁰ Columbia Center for Human Development, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York. Electronic address: jq2240@cumc.columbia.edu.

PMID: 36740200
PMCID: PMC10200757 (available on 2024-06-01)
DOI: 10.1053/j.gastro.2023.01.037

Abstract

Background & aims: Transformation of stem/progenitor cells has been associated with tumorigenesis in multiple tissues, but stem cells in the stomach have been hard to localize. We therefore aimed to use a combination of several markers to better target oncogenes to gastric stem cells and understand their behavior in the initial stages of gastric tumorigenesis.

Methods: Mouse models of gastric metaplasia and cancer by targeting stem/progenitor cells were generated and analyzed with techniques including reanalysis of single-cell RNA sequencing and immunostaining. Gastric cancer cell organoids were genetically manipulated with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) for functional studies. Cell division was determined by bromodeoxyuridine-chasing assay and the assessment of the orientation of the mitotic spindles. Gastric tissues from patients were examined by histopathology and immunostaining.

Results: Oncogenic insults lead to expansion of SOX9⁺ progenitor cells in the mouse stomach. Genetic lineage tracing and organoid culture studies show that SOX9⁺ gastric epithelial cells overlap with SOX2⁺ progenitors and include stem cells that can self-renew and differentiate to generate all gastric epithelial cells. Moreover, oncogenic targeting of SOX9⁺SOX2⁺ cells leads to invasive gastric cancer in our novel mouse model (Sox2-CreERT;Sox9-loxp(66)-rtTA-T2A-Flpo-IRES-loxp(71);Kras(Frt-STOP-Frt-G12D);P53^R172H), which combines Cre-loxp and Flippase-Frt genetic recombination systems. Sox9 deletion impedes the expansion of gastric progenitor cells and blocks neoplasia after Kras activation. Although Sox9 is not required for maintaining tissue homeostasis where asymmetric division predominates, loss of Sox9 in the setting of Kras activation leads to reduced symmetric cell division and effectively attenuates the Kras-dependent expansion of stem/progenitor cells. Similarly, Sox9 deletion in gastric cancer organoids reduces symmetric cell division, organoid number, and organoid size. In patients with gastric cancer, high levels of SOX9 are associated with recurrence and poor prognosis.

Conclusion: SOX9 marks gastric stem cells and modulates biased symmetric cell division, which appears to be required for the malignant transformation of gastric stem cells.

Keywords: Gastric Cancer; Metaplasia; Mouse Model; Neoplasia; SOX2.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Carcinogenesis / pathology
Cell Division
Cell Proliferation
Cell Transformation, Neoplastic / pathology
Mice
Proto-Oncogene Proteins p21(ras)* / genetics
Proto-Oncogene Proteins p21(ras)* / metabolism
Stem Cells / metabolism
Stomach Neoplasms* / pathology

Substances

Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding