Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis

Cell Stem Cell. 2016 Apr 7;18(4):441-55. doi: 10.1016/j.stem.2016.03.016.

Abstract

The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin-like kinase-1 (Dclk1) labels a rare population of long-lived, quiescent pancreatic cells. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In vivo, Dclk1+ cells are necessary for pancreatic regeneration following injury and chronic inflammation. Accordingly, their loss has detrimental effects after cerulein-induced pancreatitis. Expression of mutant Kras in Dclk1+ cells does not affect their quiescence or longevity. However, experimental pancreatitis converts Kras mutant Dclk1+ cells into potent cancer-initiating cells. As a potential effector of Kras, Dclk1 contributes functionally to the pathogenesis of pancreatic cancer. Taken together, these observations indicate that Dclk1 marks quiescent pancreatic progenitors that are candidates for the origin of pancreatic cancer.

Publication types

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

MeSH terms

  • Administration, Oral
  • Animals
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology
  • Carcinoma, Pancreatic Ductal / chemically induced
  • Carcinoma, Pancreatic Ductal / etiology
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Proliferation
  • Mice
  • Organoids / cytology
  • Organoids / growth & development
  • Pancreatic Neoplasms / chemically induced
  • Pancreatic Neoplasms / etiology
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology*
  • Pancreatitis / chemically induced
  • Pancreatitis / complications
  • Pancreatitis / metabolism*
  • Pancreatitis / pathology*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Tamoxifen / administration & dosage

Substances

  • Tamoxifen
  • Dclk1 protein, mouse
  • Protein-Serine-Threonine Kinases