ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis
- Lidong Wang1,2,
- Huibin Yang1,2,
- Ethan V. Abel1,2,
- Gina M. Ney2,3,
- Phillip L. Palmbos2,4,
- Filip Bednar1,
- Yaqing Zhang1,
- Jacob Leflein1,2,
- Meghna Waghray1,2,
- Scott Owens5,
- John E. Wilkinson6,
- Jayendra Prasad2,7,8,
- Mats Ljungman2,7,8,
- Andrew D. Rhim4,
- Marina Pasca di Magliano1,9 and
- Diane M. Simeone1,2,8
- 1Department of Surgery,
- 2Translational Oncology Program,
- 3Department of Pediatrics,
- 4Department of Internal Medicine,
- 5Department of Pathology,
- 6Department of Laboratory Animal Medicine,
- 7Department of Radiation Oncology,
- 8Department of Molecular and Integrative Physiology,
- 9Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA
- Corresponding author: simeone{at}med.umich.edu
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 β-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 results delineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.253591.114.
Freely available online through the Genes & Development Open Access option.
- Received October 2, 2014.
- Accepted December 1, 2014.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0.