ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis

Lidong Wang; Huibin Yang; Ethan V. Abel; Gina M. Ney; Phillip L. Palmbos; Filip Bedna; Yaqing Zhang; Jacob Leflein; Meghna Waghray; Scott Owens; John E. Wilkinson; Jayendra Prasad; Mats Ljungman; Andrew D. Rhim; Marina Pasca Di Magliano; Diane M. Simeone

doi:10.1101/gad.253591.114

ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis

Lidong Wang, Huibin Yang, Ethan V. Abel, Gina M. Ney, Phillip L. Palmbos, Filip Bedna, Yaqing Zhang, Jacob Leflein, Meghna Waghray, Scott Owens, John E. Wilkinson, Jayendra Prasad, Mats Ljungman, Andrew D. Rhim, Marina Pasca Di Magliano, Diane M. Simeone

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58 Scopus citations

Abstract

The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 [tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of b-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These resultsdelineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.

Original language	English (US)
Pages (from-to)	171-183
Number of pages	13
Journal	Genes and Development
Volume	29
Issue number	2
DOIs	https://doi.org/10.1101/gad.253591.114
State	Published - Jan 15 2015
Externally published	Yes

Keywords

Epithelial–mesenchymal transition
Metastasis
Pancreatic ductal adenocarcinoma

ASJC Scopus subject areas

Genetics
Developmental Biology

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10.1101/gad.253591.114

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Wang, L., Yang, H., Abel, E. V., Ney, G. M., Palmbos, P. L., Bedna, F., Zhang, Y., Leflein, J., Waghray, M., Owens, S., Wilkinson, J. E., Prasad, J., Ljungman, M., Rhim, A. D., Di Magliano, M. P., & Simeone, D. M. (2015). ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis. Genes and Development, 29(2), 171-183. https://doi.org/10.1101/gad.253591.114

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abstract = "The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 [tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of b-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These resultsdelineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.",

keywords = "Epithelial–mesenchymal transition, Metastasis, Pancreatic ductal adenocarcinoma",

author = "Lidong Wang and Huibin Yang and Abel, {Ethan V.} and Ney, {Gina M.} and Palmbos, {Phillip L.} and Filip Bedna and Yaqing Zhang and Jacob Leflein and Meghna Waghray and Scott Owens and Wilkinson, {John E.} and Jayendra Prasad and Mats Ljungman and Rhim, {Andrew D.} and {Di Magliano}, {Marina Pasca} and Simeone, {Diane M.}",

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AU - Ney, Gina M.

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AU - Bedna, Filip

AU - Zhang, Yaqing

AU - Leflein, Jacob

AU - Waghray, Meghna

AU - Owens, Scott

AU - Wilkinson, John E.

AU - Prasad, Jayendra

AU - Ljungman, Mats

AU - Rhim, Andrew D.

AU - Di Magliano, Marina Pasca

AU - Simeone, Diane M.

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N2 - The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 [tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of b-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These resultsdelineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.

AB - The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 [tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of b-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These resultsdelineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.

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KW - Metastasis

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ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis

Abstract

Keywords

ASJC Scopus subject areas

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