ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis
- Lidong Wang1,2,
- Huibin Yang3,
- Andrea Zamperone1,2,
- Daniel Diolaiti1,2,
- Phillip L. Palmbos4,
- Ethan V. Abel5,
- Vinee Purohit1,2,
- Igor Dolgalev2,
- Andrew D. Rhim6,
- Mats Ljungman3,
- Christina H. Hadju7,
- Christopher J. Halbrook5,
- Dafna Bar-Sagi2,8,9,
- Marina Pasca di Magliano10,11,
- Howard C. Crawford4,5 and
- Diane M. Simeone1,2,7
- 1Department of Surgery, New York University School of Medicine, New York, New York 10016, USA;
- 2Perlmutter Cancer Center, NYU Langone Medical Center, New York University, New York, New York 10016, USA;
- 3Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA;
- 4Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA;
- 5Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA;
- 6Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
- 7Department of Pathology, New York University School of Medicine, New York, New York 10016, USA;
- 8Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA;
- 9Department of Medicine, New York University School of Medicine, New York, New York 10016, USA;
- 10Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA;
- 11Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA
- Corresponding author: diane.simeone{at}nyulangone.org
Abstract
Pancreatic adenocarcinoma (PDA) is an aggressive disease driven by oncogenic KRAS and characterized by late diagnosis and therapeutic resistance. Here we show that deletion of the ataxia-telangiectasia group D-complementing (Atdc) gene, whose human homolog is up-regulated in the majority of pancreatic adenocarcinoma, completely prevents PDA development in the context of oncogenic KRAS. ATDC is required for KRAS-driven acinar–ductal metaplasia (ADM) and its progression to pancreatic intraepithelial neoplasia (PanIN). As a result, mice lacking ATDC are protected from developing PDA. Mechanistically, we show ATDC promotes ADM progression to PanIN through activation of β-catenin signaling and subsequent SOX9 up-regulation. These results provide new insight into PDA initiation and reveal ATDC as a potential target for preventing early tumor-initiating events.
Keywords
- pancreatic ductal adenocarcinoma
- KRAS
- acinar-to-ductal metaplasia
- PanIN lesion
- ATDC
- TRIM29
- SOX9
- β-catenin
Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.323303.118.
- Received December 5, 2018.
- Accepted April 8, 2019.
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