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

Authors

C. Benedikt Westphalen, Columbia University Irving Medical Center
Samuel Asfaha, Columbia University Irving Medical CenterFollow
Yoku Hayakawa, Columbia University Irving Medical Center
Yoshihiro Takemoto, Columbia University Irving Medical Center
Dana J. Lukin, Columbia University Irving Medical Center
Andreas H. Nuber, Klinikum rechts der Isar der Technischen Universität München
Anna Brandtner, Klinikum rechts der Isar der Technischen Universität München
Wanda Setlik, Columbia University Irving Medical Center
Helen Remotti, Columbia University Irving Medical Center
Ashlesha Muley, Columbia University Irving Medical Center
Xiaowei Chen, Columbia University Irving Medical Center
Randal May, University of Oklahoma
Courtney W. Houchen, University of Oklahoma
James G. Fox, Massachusetts Institute of Technology
Michael D. Gershon, Columbia University Irving Medical Center
Michael Quante, Klinikum rechts der Isar der Technischen Universität München
Timothy C. Wang, Columbia University Irving Medical Center

Document Type

Article

Publication Date

3-3-2014

Journal

Journal of Clinical Investigation

Volume

124

Issue

3

First Page

1283

Last Page

1295

URL with Digital Object Identifier

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.