Long-lived intestinal tuft cells serve as colon cancer-initiating cells

J Clin Invest. 2014 Mar;124(3):1283-95. doi: 10.1172/JCI73434.

Abstract

Doublecortin-like kinase 1 protein (DCLK1) is a gastrointestinal tuft cell marker that has been proposed to identify quiescent and tumor growth-sustaining stem cells. DCLK1⁺ tuft cells are increased in inflammation-induced carcinogenesis; however, the role of these cells within the gastrointestinal epithelium and their potential as cancer-initiating cells are poorly understood. Here, using a BAC-CreERT-dependent genetic lineage-tracing strategy, we determined that a subpopulation of DCLK1⁺ cells is extremely long lived and possesses rare stem cell abilities. Moreover, genetic ablation of Dclk1 revealed that DCLK1⁺ tuft cells contribute to recovery following intestinal and colonic injury. Surprisingly, conditional knockdown of the Wnt regulator APC in DCLK1⁺ cells was not sufficient to drive colonic carcinogenesis under normal conditions; however, dextran sodium sulfate-induced (DSS-induced) colitis promoted the development of poorly differentiated colonic adenocarcinoma in mice lacking APC in DCLK1⁺ cells. Importantly, colonic tumor formation occurred even when colitis onset was delayed for up to 3 months after induced APC loss in DCLK1⁺ cells. Thus, our data define an intestinal DCLK1⁺ tuft cell population that is long lived, quiescent, and important for intestinal homeostasis and regeneration. Long-lived DCLK1⁺ cells maintain quiescence even following oncogenic mutation, but are activated by tissue injury and can serve to initiate colon cancer.

Publication types

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

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Animals
  • Cell Lineage
  • Cells, Cultured
  • Colon / immunology
  • Colon / innervation
  • Colon / pathology*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Diphtheria Toxin / pharmacology
  • Homeostasis
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / innervation
  • Intestinal Mucosa / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Knockout
  • Neoplastic Stem Cells / physiology*
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptors, G-Protein-Coupled / metabolism

Substances

  • Diphtheria Toxin
  • Lgr5 protein, mouse
  • Receptors, G-Protein-Coupled
  • Dcamkl1 protein, mouse
  • Protein-Serine-Threonine Kinases