Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis

C. Benedikt Westphalen; Yoshihiro Takemoto; Takayuki Tanaka; Marina Macchini; Zhengyu Jiang; Bernhard W. Renz; Xiaowei Chen; Steffen Ormanns; Karan Nagar; Yagnesh Tailor; Randal May; Youngjin Cho; Samuel Asfaha; Daniel L. Worthley; Yoku Hayakawa; Aleksandra M. Urbanska; Michael Quante; Maximilian Reichert; Joshua Broyde; Prem S. Subramaniam; Helen Remotti; Gloria H. Su; Anil K. Rustgi; Richard A. Friedman; Barry Honig; Andrea Califano; Courtney W. Houchen; Kenneth P. Olive; Timothy C. Wang

doi:10.1016/j.stem.2016.03.016

Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis

C. Benedikt Westphalen, Yoshihiro Takemoto, Takayuki Tanaka, Marina Macchini, Zhengyu Jiang, Bernhard W. Renz, Xiaowei Chen, Steffen Ormanns, Karan Nagar, Yagnesh Tailor, Randal May, Youngjin Cho, Samuel Asfaha, Daniel L. Worthley, Yoku Hayakawa, Aleksandra M. Urbanska, Michael Quante, Maximilian Reichert, Joshua Broyde, Prem S. SubramaniamHelen Remotti, Gloria H. Su, Anil K. Rustgi, Richard A. Friedman, Barry Honig, Andrea Califano, Courtney W. Houchen, Kenneth P. Olive, Timothy C. Wang

Research output: Contribution to journal › Article › peer-review

179 Citations (Scopus)

Abstract

The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin-like kinase-1 (Dclk1) labels a rare population of long-lived, quiescent pancreatic cells. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In vivo, Dclk1+ cells are necessary for pancreatic regeneration following injury and chronic inflammation. Accordingly, their loss has detrimental effects after cerulein-induced pancreatitis. Expression of mutant Kras in Dclk1+ cells does not affect their quiescence or longevity. However, experimental pancreatitis converts Kras mutant Dclk1+ cells into potent cancer-initiating cells. As a potential effector of Kras, Dclk1 contributes functionally to the pathogenesis of pancreatic cancer. Taken together, these observations indicate that Dclk1 marks quiescent pancreatic progenitors that are candidates for the origin of pancreatic cancer.

Original language	English
Pages (from-to)	441-455
Number of pages	15
Journal	Cell Stem Cell
Volume	18
Issue number	4
DOIs	https://doi.org/10.1016/j.stem.2016.03.016
Publication status	Published or Issued - 7 Apr 2016
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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Westphalen, C. B., Takemoto, Y., Tanaka, T., Macchini, M., Jiang, Z., Renz, B. W., Chen, X., Ormanns, S., Nagar, K., Tailor, Y., May, R., Cho, Y., Asfaha, S., Worthley, D. L., Hayakawa, Y., Urbanska, A. M., Quante, M., Reichert, M., Broyde, J., ... Wang, T. C. (2016). Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis. Cell Stem Cell, 18(4), 441-455. https://doi.org/10.1016/j.stem.2016.03.016

@article{56ce121b98724dbdb972728e0719dcfa,

title = "Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis",

abstract = "The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin-like kinase-1 (Dclk1) labels a rare population of long-lived, quiescent pancreatic cells. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In vivo, Dclk1+ cells are necessary for pancreatic regeneration following injury and chronic inflammation. Accordingly, their loss has detrimental effects after cerulein-induced pancreatitis. Expression of mutant Kras in Dclk1+ cells does not affect their quiescence or longevity. However, experimental pancreatitis converts Kras mutant Dclk1+ cells into potent cancer-initiating cells. As a potential effector of Kras, Dclk1 contributes functionally to the pathogenesis of pancreatic cancer. Taken together, these observations indicate that Dclk1 marks quiescent pancreatic progenitors that are candidates for the origin of pancreatic cancer.",

author = "Westphalen, {C. Benedikt} and Yoshihiro Takemoto and Takayuki Tanaka and Marina Macchini and Zhengyu Jiang and Renz, {Bernhard W.} and Xiaowei Chen and Steffen Ormanns and Karan Nagar and Yagnesh Tailor and Randal May and Youngjin Cho and Samuel Asfaha and Worthley, {Daniel L.} and Yoku Hayakawa and Urbanska, {Aleksandra M.} and Michael Quante and Maximilian Reichert and Joshua Broyde and Subramaniam, {Prem S.} and Helen Remotti and Su, {Gloria H.} and Rustgi, {Anil K.} and Friedman, {Richard A.} and Barry Honig and Andrea Califano and Houchen, {Courtney W.} and Olive, {Kenneth P.} and Wang, {Timothy C.}",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = apr,

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doi = "10.1016/j.stem.2016.03.016",

language = "English",

volume = "18",

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Westphalen, CB, Takemoto, Y, Tanaka, T, Macchini, M, Jiang, Z, Renz, BW, Chen, X, Ormanns, S, Nagar, K, Tailor, Y, May, R, Cho, Y, Asfaha, S, Worthley, DL, Hayakawa, Y, Urbanska, AM, Quante, M, Reichert, M, Broyde, J, Subramaniam, PS, Remotti, H, Su, GH, Rustgi, AK, Friedman, RA, Honig, B, Califano, A, Houchen, CW, Olive, KP & Wang, TC 2016, 'Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis', Cell Stem Cell, vol. 18, no. 4, pp. 441-455. https://doi.org/10.1016/j.stem.2016.03.016

TY - JOUR

T1 - Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis

AU - Westphalen, C. Benedikt

AU - Takemoto, Yoshihiro

AU - Tanaka, Takayuki

AU - Macchini, Marina

AU - Jiang, Zhengyu

AU - Renz, Bernhard W.

AU - Chen, Xiaowei

AU - Ormanns, Steffen

AU - Nagar, Karan

AU - Tailor, Yagnesh

AU - May, Randal

AU - Cho, Youngjin

AU - Asfaha, Samuel

AU - Worthley, Daniel L.

AU - Hayakawa, Yoku

AU - Urbanska, Aleksandra M.

AU - Quante, Michael

AU - Reichert, Maximilian

AU - Broyde, Joshua

AU - Subramaniam, Prem S.

AU - Remotti, Helen

AU - Su, Gloria H.

AU - Rustgi, Anil K.

AU - Friedman, Richard A.

AU - Honig, Barry

AU - Califano, Andrea

AU - Houchen, Courtney W.

AU - Olive, Kenneth P.

AU - Wang, Timothy C.

PY - 2016/4/7

Y1 - 2016/4/7

N2 - The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin-like kinase-1 (Dclk1) labels a rare population of long-lived, quiescent pancreatic cells. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In vivo, Dclk1+ cells are necessary for pancreatic regeneration following injury and chronic inflammation. Accordingly, their loss has detrimental effects after cerulein-induced pancreatitis. Expression of mutant Kras in Dclk1+ cells does not affect their quiescence or longevity. However, experimental pancreatitis converts Kras mutant Dclk1+ cells into potent cancer-initiating cells. As a potential effector of Kras, Dclk1 contributes functionally to the pathogenesis of pancreatic cancer. Taken together, these observations indicate that Dclk1 marks quiescent pancreatic progenitors that are candidates for the origin of pancreatic cancer.

AB - The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin-like kinase-1 (Dclk1) labels a rare population of long-lived, quiescent pancreatic cells. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In vivo, Dclk1+ cells are necessary for pancreatic regeneration following injury and chronic inflammation. Accordingly, their loss has detrimental effects after cerulein-induced pancreatitis. Expression of mutant Kras in Dclk1+ cells does not affect their quiescence or longevity. However, experimental pancreatitis converts Kras mutant Dclk1+ cells into potent cancer-initiating cells. As a potential effector of Kras, Dclk1 contributes functionally to the pathogenesis of pancreatic cancer. Taken together, these observations indicate that Dclk1 marks quiescent pancreatic progenitors that are candidates for the origin of pancreatic cancer.

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U2 - 10.1016/j.stem.2016.03.016

DO - 10.1016/j.stem.2016.03.016

M3 - Article

C2 - 27058937

AN - SCOPUS:84962822324

SN - 1934-5909

VL - 18

SP - 441

EP - 455

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 4

ER -

Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis

Abstract

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