| First Author | Westphalen CB | Year | 2014 |
| Journal | J Clin Invest | Volume | 124 |
| Issue | 3 | Pages | 1283-95 |
| PubMed ID | 24487592 | Mgi Jnum | J:209426 |
| Mgi Id | MGI:5567852 | Doi | 10.1172/JCI73434 |
| Citation | Westphalen CB, et al. (2014) Long-lived intestinal tuft cells serve as colon cancer-initiating cells. J Clin Invest 124(3):1283-95 |
| abstractText | 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. |
