Long-lived intestinal tuft cells serve as colon... : Journal of Clinical Investigation (original) (raw)

Benedikt C. Westphalen
Samuel Asfaha
Yoku Hayakawa
Yoshihiro Takemoto
Dana J. Lukin
Andreas H. Nuber
Anna Brandtner
Wanda Setlik
Helen Remotti
Ashlesha Muley
Xiaowei Chen
Randal May
Courtney W. Houchen
James G. Fox
Michael D. Gershon
Michael Quante
Timothy C. Wang

Journal of Clinical Investigation

124

(

)

1283

1295

March 2014

| DOI: 10.1172/JCI73434

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.