Tuft Cells Inhibit Pancreatic Tumorigenesis in Mice by Producing Prostaglandin D 2

Gastroenterology. 2020 Nov;159(5):1866-1881.e8. doi: 10.1053/j.gastro.2020.07.037. Epub 2020 Jul 24.

Abstract

Background & aims: Development of pancreatic ductal adenocarcinoma (PDA) involves acinar to ductal metaplasia and genesis of tuft cells. It has been a challenge to study these rare cells because of the lack of animal models. We investigated the role of tuft cells in pancreatic tumorigenesis.

Methods: We performed studies with LSL-KrasG12D/+;Ptf1aCre/+ mice (KC; develop pancreatic tumors), KC mice crossed with mice with pancreatic disruption of Pou2f3 (KPouC mice; do not develop tuft cells), or mice with pancreatic disruption of the hematopoietic prostaglandin D synthase gene (Hpgds, KHC mice) and wild-type mice. Mice were allowed to age or were given caerulein to induce pancreatitis; pancreata were collected and analyzed by histology, immunohistochemistry, RNA sequencing, ultrastructural microscopy, and metabolic profiling. We performed laser-capture dissection and RNA-sequencing analysis of pancreatic tissues from 26 patients with pancreatic intraepithelial neoplasia (PanIN), 19 patients with intraductal papillary mucinous neoplasms (IPMNs), and 197 patients with PDA.

Results: Pancreata from KC mice had increased formation of tuft cells and higher levels of prostaglandin D2 than wild-type mice. Pancreas-specific deletion of POU2F3 in KC mice (KPouC mice) resulted in a loss of tuft cells and accelerated tumorigenesis. KPouC mice had increased fibrosis and activation of immune cells after administration of caerulein. Pancreata from KPouC and KHC mice had significantly lower levels of prostaglandin D2, compared with KC mice, and significantly increased numbers of PanINs and PDAs. KPouC and KHC mice had increased pancreatic injury after administration of caerulein, significantly less normal tissue, more extracellular matrix deposition, and higher PanIN grade than KC mice. Human PanIN and intraductal papillary mucinous neoplasm had gene expression signatures associated with tuft cells and increased expression of Hpgds messenger RNA compared with PDA.

Conclusions: In mice with KRAS-induced pancreatic tumorigenesis, loss of tuft cells accelerates tumorigenesis and increases the severity of caerulein-induced pancreatic injury, via decreased production of prostaglandin D2. These data are consistent with the hypothesis that tuft cells are a metaplasia-induced tumor attenuating cell type.

Keywords: COX1; COX2; Eicosanoids; Inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Carcinoma, Pancreatic Ductal / prevention & control*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Ceruletide
  • Disease Models, Animal
  • Energy Metabolism
  • Fibrosis
  • Humans
  • Interleukins / genetics
  • Interleukins / metabolism
  • Intramolecular Oxidoreductases / genetics
  • Intramolecular Oxidoreductases / metabolism
  • Mice, Transgenic
  • Mutation
  • Octamer Transcription Factors / genetics
  • Octamer Transcription Factors / metabolism
  • Pancreas / metabolism*
  • Pancreas / pathology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / prevention & control*
  • Pancreatitis / chemically induced
  • Pancreatitis / genetics
  • Pancreatitis / metabolism
  • Pancreatitis / pathology
  • Prostaglandin D2 / metabolism*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Interleukins
  • Mydgf protein, mouse
  • Octamer Transcription Factors
  • Pou2f3 protein, mouse
  • Transcription Factors
  • transcription factor PTF1
  • Ceruletide
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • Intramolecular Oxidoreductases
  • HPGDS protein, mouse
  • Prostaglandin D2