Novel role of pancreatic differentiation 2 in facilitating self-renewal and drug resistance of pancreatic cancer stem cells

A. P. Vaz; M. P. Ponnusamy; S. Rachagani; P. Dey; A. K. Ganti; S. K. Batra

doi:10.1038/bjc.2014.152

Novel role of pancreatic differentiation 2 in facilitating self-renewal and drug resistance of pancreatic cancer stem cells

A. P. Vaz, M. P. Ponnusamy, S. Rachagani, P. Dey, A. K. Ganti, S. K. Batra

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

36 Scopus citations

Abstract

Background: Cancer stem cells (CSCs) contribute towards disease aggressiveness and drug resistance. Specific identification of CSC maintenance genes and targeting can improve the efficiency of currently available treatment modalities. Pancreatic differentiation 2 (PD2) has a major role in the self-renewal of mouse embryonic stem cells. In the present study, we investigated the role of PD2 in pancreatic CSCs.Methods:Characterisation of CSCs and non-CSCs from mouse models, pancreatic cancer cells and human tissues by CSC and self-renewal marker analysis using confocal assay. Effect of PD2 knockdown in CSCs (after gemcitabine treatment) was studied by immunoblot and apoptosis assays.Results:A subpopulation of cells displayed PD2 overexpression in mouse (Kras G12D; Pdx1-Cre and Kras G12D; Trp53 R172H/+; Pdx1-Cre) and human pancreatic tumours, which co-express CSC markers. Cancer stem cells exhibited elevated expression of PD2 and self-renewal markers, such as Oct3/4, Shh and β-catenin. Gemcitabine treatment maintained the CSC population with simultaneous maintenance of PD2 and CSC marker expression. Knockdown of PD2 in CSCs resulted in reduced viability of cells and enhanced apoptosis along with abrogated expression of CD133 and MDR2.Conclusions:Our results suggest that PD2 is a novel CSC maintenance protein, loss of which renders the CSCs more susceptible to drug-induced cell death.

Original language	English (US)
Pages (from-to)	486-496
Number of pages	11
Journal	British journal of cancer
Volume	111
Issue number	3
DOIs	https://doi.org/10.1038/bjc.2014.152
State	Published - Jul 29 2014

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1038/bjc.2014.152

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@article{97a03d50471a4d7a9721248a7213b870,

title = "Novel role of pancreatic differentiation 2 in facilitating self-renewal and drug resistance of pancreatic cancer stem cells",

abstract = "Background: Cancer stem cells (CSCs) contribute towards disease aggressiveness and drug resistance. Specific identification of CSC maintenance genes and targeting can improve the efficiency of currently available treatment modalities. Pancreatic differentiation 2 (PD2) has a major role in the self-renewal of mouse embryonic stem cells. In the present study, we investigated the role of PD2 in pancreatic CSCs.Methods:Characterisation of CSCs and non-CSCs from mouse models, pancreatic cancer cells and human tissues by CSC and self-renewal marker analysis using confocal assay. Effect of PD2 knockdown in CSCs (after gemcitabine treatment) was studied by immunoblot and apoptosis assays.Results:A subpopulation of cells displayed PD2 overexpression in mouse (Kras G12D; Pdx1-Cre and Kras G12D; Trp53 R172H/+; Pdx1-Cre) and human pancreatic tumours, which co-express CSC markers. Cancer stem cells exhibited elevated expression of PD2 and self-renewal markers, such as Oct3/4, Shh and β-catenin. Gemcitabine treatment maintained the CSC population with simultaneous maintenance of PD2 and CSC marker expression. Knockdown of PD2 in CSCs resulted in reduced viability of cells and enhanced apoptosis along with abrogated expression of CD133 and MDR2.Conclusions:Our results suggest that PD2 is a novel CSC maintenance protein, loss of which renders the CSCs more susceptible to drug-induced cell death.",

author = "Vaz, {A. P.} and Ponnusamy, {M. P.} and S. Rachagani and P. Dey and Ganti, {A. K.} and Batra, {S. K.}",

note = "Funding Information: We acknowledge the invaluable technical support from Kavita Mallya. We acknowledge the support extended by Victoria Smith, Charles Kuzynski, PhD and Philip Hexley, PhD of the flow cytometry facility at UNMC. The UNMC Flow Cytometry Research Facility is administrated through the Office of the Vice Chancellor for Research and supported by state funds from the Nebraska Research Initiative (NRI) and The Fred and Pamela Buffet Cancer Center{\textquoteright}s National Cancer Institute Cancer Support Grant. Major instrumentation has been provided by the Office of the Vice Chancellor for Research, The University of Nebraska Foundation, the Nebraska Banker{\textquoteright}s Fund, and by the NIH-NCRR Shared Instrument Program. We also thank Janice A Taylor and James R Talaska, of the confocal laser scanning microscope core facility at UNMC, for their support. This work was supported by grants from the National Institutes of Health (EDRN UO1CA111294, SPORE P50CA127297, TMEN U54CA163120 and R03 CA167342) VA Career Development Award and the Elsa U Pardee Foundation (2013).",

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doi = "10.1038/bjc.2014.152",

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volume = "111",

pages = "486--496",

journal = "British journal of cancer",

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T1 - Novel role of pancreatic differentiation 2 in facilitating self-renewal and drug resistance of pancreatic cancer stem cells

AU - Vaz, A. P.

AU - Ponnusamy, M. P.

AU - Rachagani, S.

AU - Dey, P.

AU - Ganti, A. K.

AU - Batra, S. K.

N1 - Funding Information: We acknowledge the invaluable technical support from Kavita Mallya. We acknowledge the support extended by Victoria Smith, Charles Kuzynski, PhD and Philip Hexley, PhD of the flow cytometry facility at UNMC. The UNMC Flow Cytometry Research Facility is administrated through the Office of the Vice Chancellor for Research and supported by state funds from the Nebraska Research Initiative (NRI) and The Fred and Pamela Buffet Cancer Center’s National Cancer Institute Cancer Support Grant. Major instrumentation has been provided by the Office of the Vice Chancellor for Research, The University of Nebraska Foundation, the Nebraska Banker’s Fund, and by the NIH-NCRR Shared Instrument Program. We also thank Janice A Taylor and James R Talaska, of the confocal laser scanning microscope core facility at UNMC, for their support. This work was supported by grants from the National Institutes of Health (EDRN UO1CA111294, SPORE P50CA127297, TMEN U54CA163120 and R03 CA167342) VA Career Development Award and the Elsa U Pardee Foundation (2013).

PY - 2014/7/29

Y1 - 2014/7/29

N2 - Background: Cancer stem cells (CSCs) contribute towards disease aggressiveness and drug resistance. Specific identification of CSC maintenance genes and targeting can improve the efficiency of currently available treatment modalities. Pancreatic differentiation 2 (PD2) has a major role in the self-renewal of mouse embryonic stem cells. In the present study, we investigated the role of PD2 in pancreatic CSCs.Methods:Characterisation of CSCs and non-CSCs from mouse models, pancreatic cancer cells and human tissues by CSC and self-renewal marker analysis using confocal assay. Effect of PD2 knockdown in CSCs (after gemcitabine treatment) was studied by immunoblot and apoptosis assays.Results:A subpopulation of cells displayed PD2 overexpression in mouse (Kras G12D; Pdx1-Cre and Kras G12D; Trp53 R172H/+; Pdx1-Cre) and human pancreatic tumours, which co-express CSC markers. Cancer stem cells exhibited elevated expression of PD2 and self-renewal markers, such as Oct3/4, Shh and β-catenin. Gemcitabine treatment maintained the CSC population with simultaneous maintenance of PD2 and CSC marker expression. Knockdown of PD2 in CSCs resulted in reduced viability of cells and enhanced apoptosis along with abrogated expression of CD133 and MDR2.Conclusions:Our results suggest that PD2 is a novel CSC maintenance protein, loss of which renders the CSCs more susceptible to drug-induced cell death.

AB - Background: Cancer stem cells (CSCs) contribute towards disease aggressiveness and drug resistance. Specific identification of CSC maintenance genes and targeting can improve the efficiency of currently available treatment modalities. Pancreatic differentiation 2 (PD2) has a major role in the self-renewal of mouse embryonic stem cells. In the present study, we investigated the role of PD2 in pancreatic CSCs.Methods:Characterisation of CSCs and non-CSCs from mouse models, pancreatic cancer cells and human tissues by CSC and self-renewal marker analysis using confocal assay. Effect of PD2 knockdown in CSCs (after gemcitabine treatment) was studied by immunoblot and apoptosis assays.Results:A subpopulation of cells displayed PD2 overexpression in mouse (Kras G12D; Pdx1-Cre and Kras G12D; Trp53 R172H/+; Pdx1-Cre) and human pancreatic tumours, which co-express CSC markers. Cancer stem cells exhibited elevated expression of PD2 and self-renewal markers, such as Oct3/4, Shh and β-catenin. Gemcitabine treatment maintained the CSC population with simultaneous maintenance of PD2 and CSC marker expression. Knockdown of PD2 in CSCs resulted in reduced viability of cells and enhanced apoptosis along with abrogated expression of CD133 and MDR2.Conclusions:Our results suggest that PD2 is a novel CSC maintenance protein, loss of which renders the CSCs more susceptible to drug-induced cell death.

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Novel role of pancreatic differentiation 2 in facilitating self-renewal and drug resistance of pancreatic cancer stem cells

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