Long-lived intestinal tuft cells serve as colon cancer-initiating cells.
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.
C Benedikt
CB
Westphalen
Samuel
S
Asfaha
Yoku
Y
Hayakawa
Yoshihiro
Y
Takemoto
Dana J
DJ
Lukin
Andreas H
AH
Nuber
Anna
A
Brandtner
Wanda
W
Setlik
Helen
H
Remotti
Ashlesha
A
Muley
Xiaowei
X
Chen
Randal
R
May
Courtney W
CW
Houchen
James G
JG
Fox
Michael D
MD
Gershon
Michael
M
Quante
Timothy C
TC
Wang
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D019070:Cell Lineage; D002478:Cells, Cultured; D003106:Colon / Q000276:immunology / Q000294:innervation / Q000473:pathology*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D004167:Diphtheria Toxin / Q000494:pharmacology; D000089742:Doublecortin-Like Kinases; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000276:immunology / Q000294:innervation / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
D004167:Diphtheria Toxin; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases