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

C. Benedikt 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

Research output: Contribution to journalArticle

148 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1283-1295
Number of pages13
JournalJournal of Clinical Investigation
Volume124
Issue number3
DOIs
StatePublished - Mar 3 2014
Externally publishedYes

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Colonic Neoplasms
Protein Kinases
Colitis
Carcinogenesis
Stem Cells
Neoplasms
Dextran Sulfate
Wounds and Injuries
Regeneration
Adenocarcinoma
Homeostasis
Epithelium
Inflammation
Mutation
Growth

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Westphalen, C. B., Asfaha, S., Hayakawa, Y., Takemoto, Y., Lukin, D. J., Nuber, A. H., ... Wang, T. C. (2014). Long-lived intestinal tuft cells serve as colon cancer-initiating cells. Journal of Clinical Investigation, 124(3), 1283-1295. https://doi.org/10.1172/JCI73434

Long-lived intestinal tuft cells serve as colon cancer-initiating cells. / Westphalen, C. Benedikt; Asfaha, Samuel; Hayakawa, Yoku; Takemoto, Yoshihiro; Lukin, Dana J.; Nuber, Andreas H.; Brandtner, Anna; Setlik, Wanda; Remotti, Helen; Muley, Ashlesha; Chen, Xiaowei; May, Randal; Houchen, Courtney W.; Fox, James G.; Gershon, Michael D.; Quante, Michael; Wang, Timothy C.

In: Journal of Clinical Investigation, Vol. 124, No. 3, 03.03.2014, p. 1283-1295.

Research output: Contribution to journalArticle

Westphalen, CB, Asfaha, S, Hayakawa, Y, Takemoto, Y, Lukin, DJ, Nuber, AH, Brandtner, A, Setlik, W, Remotti, H, Muley, A, Chen, X, May, R, Houchen, CW, Fox, JG, Gershon, MD, Quante, M & Wang, TC 2014, 'Long-lived intestinal tuft cells serve as colon cancer-initiating cells', Journal of Clinical Investigation, vol. 124, no. 3, pp. 1283-1295. https://doi.org/10.1172/JCI73434
Westphalen CB, Asfaha S, Hayakawa Y, Takemoto Y, Lukin DJ, Nuber AH et al. Long-lived intestinal tuft cells serve as colon cancer-initiating cells. Journal of Clinical Investigation. 2014 Mar 3;124(3):1283-1295. https://doi.org/10.1172/JCI73434
Westphalen, C. Benedikt ; Asfaha, Samuel ; Hayakawa, Yoku ; Takemoto, Yoshihiro ; Lukin, Dana J. ; Nuber, Andreas H. ; Brandtner, Anna ; Setlik, Wanda ; Remotti, Helen ; Muley, Ashlesha ; Chen, Xiaowei ; May, Randal ; Houchen, Courtney W. ; Fox, James G. ; Gershon, Michael D. ; Quante, Michael ; Wang, Timothy C. / Long-lived intestinal tuft cells serve as colon cancer-initiating cells. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 3. pp. 1283-1295.
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AU - Asfaha, Samuel

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AU - Takemoto, Yoshihiro

AU - Lukin, Dana J.

AU - Nuber, Andreas H.

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AU - Chen, Xiaowei

AU - May, Randal

AU - Houchen, Courtney W.

AU - Fox, James G.

AU - Gershon, Michael D.

AU - Quante, Michael

AU - Wang, Timothy C.

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