DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer

Gastroenterology. 2014 Jan;146(1):245-56. doi: 10.1053/j.gastro.2013.09.050. Epub 2013 Oct 2.

Abstract

Background & aims: As in other tumor types, progression of pancreatic cancer may require a functionally unique population of cancer stem cells. Although such cells have been identified in many invasive cancers, it is not clear whether they emerge during early or late stages of tumorigenesis. Using mouse models and human pancreatic cancer cell lines, we investigated whether preinvasive pancreatic neoplasia contains a subpopulation of cells with distinct morphologies and cancer stem cell-like properties.

Methods: Pancreatic tissue samples were collected from the KC(Pdx1), KPC(Pdx1), and KC(iMist1) mouse models of pancreatic intraepithelial neoplasia (PanIN) and analyzed by confocal and electron microscopy, lineage tracing, and fluorescence-activated cell sorting. Subpopulations of human pancreatic ductal adenocarcinoma (PDAC) cells were similarly analyzed and also used in complementary DNA microarray analyses.

Results: The microtubule regulator DCLK1 marked a morphologically distinct and functionally unique population of pancreatic cancer-initiating cells. These cells displayed morphological and molecular features of gastrointestinal tuft cells. Cells that expressed DCLK1 also expressed high levels of ATAT1, HES1, HEY1, IGF1R, and ABL1, and manipulation of these pathways in PDAC cell lines inhibited their clonogenic potential. Pharmacological inhibition of γ-secretase activity reduced the abundance of these cells in murine PanIN in a manner that correlated with inhibition of PanIN progression.

Conclusions: Human PDAC cells and pancreatic neoplasms in mice contain morphologically and functionally distinct subpopulations that have cancer stem cell-like properties. These populations can be identified at the earliest stages of pancreatic tumorigenesis and provide new cellular and molecular targets for pancreatic cancer treatment and/or chemoprevention.

Keywords: ADM; AcTub; Acetylated Tubulin; Dclk1; FACS; GFP; Kras; Notch; PDAC; PanIN; TEM; acetylated α-tubulin; acinar-to-ductal metaplasia; doublecortin and Ca(2+)/calmodulin-dependent kinase-like 1; fluorescence-activated cell sorting; green fluorescent protein; mPanIN; murine pancreatic intraepithelial neoplasia; pancreatic ductal adenocarcinoma; pancreatic intraepithelial neoplasia; transmission electron microscopy.

Publication types

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

MeSH terms

  • Animals
  • Carcinoma in Situ / metabolism*
  • Carcinoma in Situ / pathology
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Transformation, Neoplastic
  • Disease Models, Animal
  • Flow Cytometry
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Microscopy, Electron
  • Neoplasm Invasiveness
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • Stem Cells / metabolism*
  • Stem Cells / pathology

Substances

  • Intracellular Signaling Peptides and Proteins
  • Dcamkl1 protein, mouse
  • DCLK1 protein, human
  • Protein-Serine-Threonine Kinases