DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer

Jennifer M. Bailey, Janivette Alsina, Zeshaan A. Rasheed, Florencia M. McAllister, Ya Yuan Fu, Ruben Plentz, Hao Zhang, Pankaj Jay Pasricha, Nabeel Bardeesy, William Matsui, Anirban Maitra, Steven D. Leach

Research output: Contribution to journalArticle

Abstract

Background & Aims As in other tumor types, progression of pancreatic cancer may require a functionally unique population of cancer stem cells. Although such cells have been identified in many invasive cancers, it is not clear whether they emerge during early or late stages of tumorigenesis. Using mouse models and human pancreatic cancer cell lines, we investigated whether preinvasive pancreatic neoplasia contains a subpopulation of cells with distinct morphologies and cancer stem cell-like properties. Methods Pancreatic tissue samples were collected from the KCPdx1, KPCPdx1, and KCiMist1 mouse models of pancreatic intraepithelial neoplasia (PanIN) and analyzed by confocal and electron microscopy, lineage tracing, and fluorescence-activated cell sorting. Subpopulations of human pancreatic ductal adenocarcinoma (PDAC) cells were similarly analyzed and also used in complementary DNA microarray analyses. Results The microtubule regulator DCLK1 marked a morphologically distinct and functionally unique population of pancreatic cancer-initiating cells. These cells displayed morphological and molecular features of gastrointestinal tuft cells. Cells that expressed DCLK1 also expressed high levels of ATAT1, HES1, HEY1, IGF1R, and ABL1, and manipulation of these pathways in PDAC cell lines inhibited their clonogenic potential. Pharmacological inhibition of γ-secretase activity reduced the abundance of these cells in murine PanIN in a manner that correlated with inhibition of PanIN progression. Conclusions Human PDAC cells and pancreatic neoplasms in mice contain morphologically and functionally distinct subpopulations that have cancer stem cell-like properties. These populations can be identified at the earliest stages of pancreatic tumorigenesis and provide new cellular and molecular targets for pancreatic cancer treatment and/or chemoprevention.

Original languageEnglish (US)
Pages (from-to)245-256
Number of pages12
JournalGastroenterology
Volume146
Issue number1
DOIs
StatePublished - Jan 2014

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Pancreatic Neoplasms
Stem Cells
Neoplastic Stem Cells
Neoplasms
Adenocarcinoma
Carcinogenesis
Population
Cell Line
Amyloid Precursor Protein Secretases
Chemoprevention
Microarray Analysis
Oligonucleotide Array Sequence Analysis
Confocal Microscopy
Microtubules
Electron Microscopy
Flow Cytometry
Complementary DNA
Pharmacology

Keywords

  • Acetylated Tubulin
  • Kras
  • Notch
  • PanIN

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Bailey, J. M., Alsina, J., Rasheed, Z. A., McAllister, F. M., Fu, Y. Y., Plentz, R., ... Leach, S. D. (2014). DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. Gastroenterology, 146(1), 245-256. https://doi.org/10.1053/j.gastro.2013.09.050

DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. / Bailey, Jennifer M.; Alsina, Janivette; Rasheed, Zeshaan A.; McAllister, Florencia M.; Fu, Ya Yuan; Plentz, Ruben; Zhang, Hao; Pasricha, Pankaj Jay; Bardeesy, Nabeel; Matsui, William; Maitra, Anirban; Leach, Steven D.

In: Gastroenterology, Vol. 146, No. 1, 01.2014, p. 245-256.

Research output: Contribution to journalArticle

Bailey, JM, Alsina, J, Rasheed, ZA, McAllister, FM, Fu, YY, Plentz, R, Zhang, H, Pasricha, PJ, Bardeesy, N, Matsui, W, Maitra, A & Leach, SD 2014, 'DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer', Gastroenterology, vol. 146, no. 1, pp. 245-256. https://doi.org/10.1053/j.gastro.2013.09.050
Bailey, Jennifer M. ; Alsina, Janivette ; Rasheed, Zeshaan A. ; McAllister, Florencia M. ; Fu, Ya Yuan ; Plentz, Ruben ; Zhang, Hao ; Pasricha, Pankaj Jay ; Bardeesy, Nabeel ; Matsui, William ; Maitra, Anirban ; Leach, Steven D. / DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. In: Gastroenterology. 2014 ; Vol. 146, No. 1. pp. 245-256.
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abstract = "Background & Aims As in other tumor types, progression of pancreatic cancer may require a functionally unique population of cancer stem cells. Although such cells have been identified in many invasive cancers, it is not clear whether they emerge during early or late stages of tumorigenesis. Using mouse models and human pancreatic cancer cell lines, we investigated whether preinvasive pancreatic neoplasia contains a subpopulation of cells with distinct morphologies and cancer stem cell-like properties. Methods Pancreatic tissue samples were collected from the KCPdx1, KPCPdx1, and KCiMist1 mouse models of pancreatic intraepithelial neoplasia (PanIN) and analyzed by confocal and electron microscopy, lineage tracing, and fluorescence-activated cell sorting. Subpopulations of human pancreatic ductal adenocarcinoma (PDAC) cells were similarly analyzed and also used in complementary DNA microarray analyses. Results The microtubule regulator DCLK1 marked a morphologically distinct and functionally unique population of pancreatic cancer-initiating cells. These cells displayed morphological and molecular features of gastrointestinal tuft cells. Cells that expressed DCLK1 also expressed high levels of ATAT1, HES1, HEY1, IGF1R, and ABL1, and manipulation of these pathways in PDAC cell lines inhibited their clonogenic potential. Pharmacological inhibition of γ-secretase activity reduced the abundance of these cells in murine PanIN in a manner that correlated with inhibition of PanIN progression. Conclusions Human PDAC cells and pancreatic neoplasms in mice contain morphologically and functionally distinct subpopulations that have cancer stem cell-like properties. These populations can be identified at the earliest stages of pancreatic tumorigenesis and provide new cellular and molecular targets for pancreatic cancer treatment and/or chemoprevention.",
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AU - Bailey, Jennifer M.

AU - Alsina, Janivette

AU - Rasheed, Zeshaan A.

AU - McAllister, Florencia M.

AU - Fu, Ya Yuan

AU - Plentz, Ruben

AU - Zhang, Hao

AU - Pasricha, Pankaj Jay

AU - Bardeesy, Nabeel

AU - Matsui, William

AU - Maitra, Anirban

AU - Leach, Steven D.

PY - 2014/1

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N2 - Background & Aims As in other tumor types, progression of pancreatic cancer may require a functionally unique population of cancer stem cells. Although such cells have been identified in many invasive cancers, it is not clear whether they emerge during early or late stages of tumorigenesis. Using mouse models and human pancreatic cancer cell lines, we investigated whether preinvasive pancreatic neoplasia contains a subpopulation of cells with distinct morphologies and cancer stem cell-like properties. Methods Pancreatic tissue samples were collected from the KCPdx1, KPCPdx1, and KCiMist1 mouse models of pancreatic intraepithelial neoplasia (PanIN) and analyzed by confocal and electron microscopy, lineage tracing, and fluorescence-activated cell sorting. Subpopulations of human pancreatic ductal adenocarcinoma (PDAC) cells were similarly analyzed and also used in complementary DNA microarray analyses. Results The microtubule regulator DCLK1 marked a morphologically distinct and functionally unique population of pancreatic cancer-initiating cells. These cells displayed morphological and molecular features of gastrointestinal tuft cells. Cells that expressed DCLK1 also expressed high levels of ATAT1, HES1, HEY1, IGF1R, and ABL1, and manipulation of these pathways in PDAC cell lines inhibited their clonogenic potential. Pharmacological inhibition of γ-secretase activity reduced the abundance of these cells in murine PanIN in a manner that correlated with inhibition of PanIN progression. Conclusions Human PDAC cells and pancreatic neoplasms in mice contain morphologically and functionally distinct subpopulations that have cancer stem cell-like properties. These populations can be identified at the earliest stages of pancreatic tumorigenesis and provide new cellular and molecular targets for pancreatic cancer treatment and/or chemoprevention.

AB - Background & Aims As in other tumor types, progression of pancreatic cancer may require a functionally unique population of cancer stem cells. Although such cells have been identified in many invasive cancers, it is not clear whether they emerge during early or late stages of tumorigenesis. Using mouse models and human pancreatic cancer cell lines, we investigated whether preinvasive pancreatic neoplasia contains a subpopulation of cells with distinct morphologies and cancer stem cell-like properties. Methods Pancreatic tissue samples were collected from the KCPdx1, KPCPdx1, and KCiMist1 mouse models of pancreatic intraepithelial neoplasia (PanIN) and analyzed by confocal and electron microscopy, lineage tracing, and fluorescence-activated cell sorting. Subpopulations of human pancreatic ductal adenocarcinoma (PDAC) cells were similarly analyzed and also used in complementary DNA microarray analyses. Results The microtubule regulator DCLK1 marked a morphologically distinct and functionally unique population of pancreatic cancer-initiating cells. These cells displayed morphological and molecular features of gastrointestinal tuft cells. Cells that expressed DCLK1 also expressed high levels of ATAT1, HES1, HEY1, IGF1R, and ABL1, and manipulation of these pathways in PDAC cell lines inhibited their clonogenic potential. Pharmacological inhibition of γ-secretase activity reduced the abundance of these cells in murine PanIN in a manner that correlated with inhibition of PanIN progression. Conclusions Human PDAC cells and pancreatic neoplasms in mice contain morphologically and functionally distinct subpopulations that have cancer stem cell-like properties. These populations can be identified at the earliest stages of pancreatic tumorigenesis and provide new cellular and molecular targets for pancreatic cancer treatment and/or chemoprevention.

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KW - Kras

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