Tff2 marks gastric corpus progenitors that give rise to pyloric metaplasia/SPEM following injury

Ruhong Tu; Hua-Long Zheng; Biyun Zheng; Qing Zhong; Jin Qian; Qian Yu; Feijing Wu; Toshiro Shiokawa; Yosuke Ochiai; Hiroki Kobayashi; Quin T Waterbury; Leah Zamechek; Youxin Gao; Satoru Takahashi; Seiya Mizuno; Chang Ming Huang; Ping Li; Yoku Hayakawa; Timothy C Wang

doi:10.1136/gutjnl-2025-337839

Tff2 marks gastric corpus progenitors that give rise to pyloric metaplasia/SPEM following injury

Gut. 2026 Apr 14:gutjnl-2025-337839. doi: 10.1136/gutjnl-2025-337839. Online ahead of print.

Authors

Ruhong Tu^{1

2}, Hua-Long Zheng^{2

3

4}, Biyun Zheng^{3

5}, Qing Zhong^{2

6}, Jin Qian³, Qian Yu⁷, Feijing Wu⁸, Toshiro Shiokawa⁹, Yosuke Ochiai³, Hiroki Kobayashi¹⁰, Quin T Waterbury³, Leah Zamechek¹¹, Youxin Gao², Satoru Takahashi¹², Seiya Mizuno¹², Chang Ming Huang¹³, Ping Li², Yoku Hayakawa¹⁴, Timothy C Wang^{15

3

16}

Affiliations

¹ Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, New York, USA.
² Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
³ Department of Medicine, Columbia University, New York, New York, USA.
⁴ Fujian Medical University, Fuzhou, Fujian, China.
⁵ Gastroenterology, Fujian Medical University Union Hospital, Fuzhou, China.
⁶ Department of Gastric Surgery, Fujian Medical University, Fuzhou, Fujian, China.
⁷ Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
⁸ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
⁹ Graduate School of Medicine, The University of Tokyo, Bunkyo, Japan.
¹⁰ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.
¹¹ Medicine, Columbia University Irving Medical Center, New York, New York, USA.
¹² Laboratory Animal Resource Center in Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan.
¹³ Department of General Surgery, Union Hospital of Fujian Medical University, Fuzhou, Fujian, China.
¹⁴ Department of Gastroenterology, The University of Tokyo, Bunkyo, Tokyo, Japan.
¹⁵ Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, New York, USA tcw21@cumc.columbia.edu.
¹⁶ College of Physicians and Surgeons, Division of Digestive and Liver Diseases, Columbia University, New York, New York, USA.

PMID: 41980762
DOI: 10.1136/gutjnl-2025-337839

Abstract

Background: Spasmolytic polypeptide-expressing metaplasia (SPEM) arises in the gastric corpus in response to oxyntic atrophy, but its cellular origin and role in gastric cancer remain unclear.

Objective: To define the cellular origin of SPEM in the gastric corpus and its relationship to gastric dysplasia and cancer progression.

Design: Tff2-CreERT2 knock-in mice were used for lineage tracing and genetic ablation to characterise Tff2⁺ corpus progenitor cells. Acute injury, chief cell ablation, H. pylori infection and Kras^G12D activation models were applied. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were performed on human gastric tissues to validate differentiation trajectories.

Results: Highly proliferative Tff2⁺ progenitors were localised to the corpus isthmus and generated multiple secretory lineages including chief cells, but lacked long-term self-renewal. Following acute injury or chief cell loss, Tff2⁺ progenitors rapidly expanded to form transient SPEM. Genetic ablation of Tff2⁺ progenitors abolished SPEM formation, whereas ablation of Lgr5-DTR- or Gif-rtTA-labelled chief cells enhanced SPEM derived from Tff2⁺ progenitors. on H. pylori infection or Kras^G12D activation, Tff2⁺ progenitors progressed to SPEM and dysplasia. Kras activation in Tff2⁺ progenitors promoted direct progression to dysplasia through acquisition of stem cell-like properties. In contrast, Kras-mutant SPEM and chief cells failed to progress to dysplasia. Human scRNA-seq and spatial transcriptomics revealed distinct differentiation trajectories from isthmus proliferating cells to SPEM or gastric cancer.

Conclusions: Tff2⁺ corpus progenitors represent a common cellular origin for SPEM and gastric dysplasia, challenge the conventional stepwise model of gastric carcinogenesis and indicate divergent differentiation programmes from Tff2⁺ progenitors.

Keywords: GASTROINTESTINAL CANCER; GASTROINTESTINAL PATHOLOGY; GASTROINTESTINAL PHYSIOLOGY.