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.
authors.affiliation: Department of Internal Medicine III, Hospital of the University of Munich D-81377, Munich, Germany; Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: C Benedikt
authors.initials: CB
authors.lastname: Westphalen
authors.affiliation: Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takemoto
authors.affiliation: Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, 40128 Bologna, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Macchini
authors.affiliation: Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich D-81377, Munich, Germany; Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Bernhard W
authors.initials: BW
authors.lastname: Renz
authors.affiliation: Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology, Hospital of the University of Munich D-81377, Munich, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Ormanns
authors.affiliation: Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Karan
authors.initials: K
authors.lastname: Nagar
authors.affiliation: Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Yagnesh
authors.initials: Y
authors.lastname: Tailor
authors.affiliation: Department of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, OK 73104, USA.
authors.forename: Randal
authors.initials: R
authors.lastname: May
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Youngjin
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Asfaha
authors.affiliation: Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Worthley
authors.affiliation: Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Urbanska
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar II, Technische Universität München, D-81675 Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Quante
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar II, Technische Universität München, D-81675 Munich, Germany; Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Reichert
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Broyde
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Prem S
authors.initials: PS
authors.lastname: Subramaniam
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Remotti
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Otolaryngology / Head & Neck Surgery, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Gloria H
authors.initials: GH
authors.lastname: Su
authors.affiliation: Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friedman
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Honig
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Otolaryngology / Head & Neck Surgery, Columbia University Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA; Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA; Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Center for Computational Biology and Bioinformatics (C2B2), Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: Department of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, OK 73104, USA.
authors.forename: Courtney W
authors.initials: CW
authors.lastname: Houchen
authors.affiliation: Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Olive
authors.affiliation: Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D000089742:Doublecortin-Like Kinases; D051379:Mice; D009940:Organoids / Q000166:cytology / Q000254:growth & development; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000008:administration & dosage
chemical_list: D013629:Tamoxifen; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases