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Long-lived intestinal tuft cells serve as colon cancer–initiating cells
Journal of Clinical Investigation (2014)
  • CB Westphalen
  • Samuel Asfaha, Western University
  • Y Hayakawa
  • Y Takemoto
  • DJ Lukin
  • AH Nuber
  • A Brandtner
  • W Setlik
  • H Remotti
  • A Muley
  • X Chen
  • R May
  • CW Houchen
  • JG Fox
  • MD Gershon
  • M Quante
  • TC Wang
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.
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Citation Information
CB Westphalen, Samuel Asfaha, Y Hayakawa, Y Takemoto, et al.. "Long-lived intestinal tuft cells serve as colon cancer–initiating cells" Journal of Clinical Investigation (2014)
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