Tff2 defines transit-amplifying pancreatic acinar progenitors that lack regenerative potential and are protective against Kras-driven carcinogenesis

Zhengyu Jiang; Feijing Wu; Pasquale Laise; Tanaka Takayuki; Fu Na; Woosook Kim; Hiroki Kobayashi; Wenju Chang; Ryota Takahashi; Giovanni Valenti; Masaki Sunagawa; Ruth A White; Marina Macchini; Bernhard W Renz; Moritz Middelhoff; Yoku Hayakawa; Zinaida A Dubeykovskaya; Xiangtian Tan; Timothy H Chu; Karan Nagar; Yagnesh Tailor; Bryana R Belin; Akanksha Anand; Samuel Asfaha; Michael O Finlayson; Alina C Iuga; Andrea Califano; Timothy C Wang

doi:10.1016/j.stem.2023.07.002

Tff2 defines transit-amplifying pancreatic acinar progenitors that lack regenerative potential and are protective against Kras-driven carcinogenesis

Cell Stem Cell. 2023 Aug 3;30(8):1091-1109.e7. doi: 10.1016/j.stem.2023.07.002.

Authors

Zhengyu Jiang¹, Feijing Wu², Pasquale Laise³, Tanaka Takayuki¹, Fu Na⁴, Woosook Kim¹, Hiroki Kobayashi¹, Wenju Chang¹, Ryota Takahashi¹, Giovanni Valenti¹, Masaki Sunagawa¹, Ruth A White⁵, Marina Macchini¹, Bernhard W Renz⁶, Moritz Middelhoff⁷, Yoku Hayakawa⁸, Zinaida A Dubeykovskaya¹, Xiangtian Tan⁹, Timothy H Chu¹, Karan Nagar¹, Yagnesh Tailor¹, Bryana R Belin¹, Akanksha Anand¹⁰, Samuel Asfaha¹¹, Michael O Finlayson⁹, Alina C Iuga¹², Andrea Califano³, Timothy C Wang¹³

Affiliations

¹ Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
² Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA; The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
³ Department of Systems Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA; DarwinHealth Inc., New York, NY, USA.
⁴ Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.
⁵ Division of Hematology and Oncology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁶ Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of General, Visceral, and Transplantation Surgery, LMU University Hospital, LMU Munich, Germany.
⁷ Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Division of Digestive and Liver Diseases, CU and Klinikum rechts der Isar, Technical University, Munich, Germany.
⁸ Graduate School of Medicine, Department of Gastroenterology, The University of Tokyo, Tokyo, Japan.
⁹ Department of Systems Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
¹⁰ Division of Digestive and Liver Diseases, Department of Medicine and Department of Gastroenterology II, Klinikum rechts der Isar, Technical University, Munich, Germany.
¹¹ Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
¹² Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
¹³ Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA. Electronic address: tcw21@columbia.edu.

PMID: 37541213
PMCID: PMC10414754 (available on 2024-08-03)
DOI: 10.1016/j.stem.2023.07.002

Abstract

While adult pancreatic stem cells are thought not to exist, it is now appreciated that the acinar compartment harbors progenitors, including tissue-repairing facultative progenitors (FPs). Here, we study a pancreatic acinar population marked by trefoil factor 2 (Tff2) expression. Long-term lineage tracing and single-cell RNA sequencing (scRNA-seq) analysis of Tff2-DTR-CreER^T2-targeted cells defines a transit-amplifying progenitor (TAP) population that contributes to normal homeostasis. Following acute and chronic injury, Tff2⁺ cells, distinct from FPs, undergo depopulation but are eventually replenished. At baseline, oncogenic Kras^G12D-targeted Tff2⁺ cells are resistant to PDAC initiation. However, Kras^G12D activation in Tff2⁺ cells leads to survival and clonal expansion following pancreatitis and a cancer stem/progenitor cell-like state. Selective ablation of Tff2⁺ cells prior to Kras^G12D activation in Mist1⁺ acinar or Dclk1⁺ FP cells results in enhanced tumorigenesis, which can be partially rescued by adenoviral Tff2 treatment. Together, Tff2 defines a pancreatic TAP population that protects against Kras-driven carcinogenesis.

Keywords: cell ablation; lineage tracing; pancreas; pancreatic ductal carcinoma; progenitor cells; regeneration; transit-amplifying cells; trefoil factor 2.

Publication types

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

MeSH terms

Acinar Cells / metabolism
Carcinogenesis / genetics
Carcinogenesis / metabolism
Carcinoma, Pancreatic Ductal* / genetics
Carcinoma, Pancreatic Ductal* / metabolism
Humans
Pancreas / metabolism
Pancreatic Neoplasms* / genetics
Trefoil Factor-2 / metabolism

Substances

Trefoil Factor-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding