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ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis.
Wang, Lidong; Yang, Huibin; Zamperone, Andrea; Diolaiti, Daniel; Palmbos, Phillip L; Abel, Ethan V; Purohit, Vinee; Dolgalev, Igor; Rhim, Andrew D; Ljungman, Mats; Hadju, Christina H; Halbrook, Christopher J; Bar-Sagi, Dafna; di Magliano, Marina Pasca; Crawford, Howard C; Simeone, Diane M.
Affiliation
  • Wang L; Department of Surgery, New York University School of Medicine, New York, New York 10016, USA.
  • Yang H; Perlmutter Cancer Center, NYU Langone Medical Center, New York University, New York, New York 10016, USA.
  • Zamperone A; Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Diolaiti D; Department of Surgery, New York University School of Medicine, New York, New York 10016, USA.
  • Palmbos PL; Perlmutter Cancer Center, NYU Langone Medical Center, New York University, New York, New York 10016, USA.
  • Abel EV; Department of Surgery, New York University School of Medicine, New York, New York 10016, USA.
  • Purohit V; Perlmutter Cancer Center, NYU Langone Medical Center, New York University, New York, New York 10016, USA.
  • Dolgalev I; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Rhim AD; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Ljungman M; Department of Surgery, New York University School of Medicine, New York, New York 10016, USA.
  • Hadju CH; Perlmutter Cancer Center, NYU Langone Medical Center, New York University, New York, New York 10016, USA.
  • Halbrook CJ; Perlmutter Cancer Center, NYU Langone Medical Center, New York University, New York, New York 10016, USA.
  • Bar-Sagi D; Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • di Magliano MP; Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Crawford HC; Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.
  • Simeone DM; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Genes Dev ; 33(11-12): 641-655, 2019 06 01.
Article in En | MEDLINE | ID: mdl-31048544
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 ß-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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pancreatic Neoplasms / Transcription Factors / Proto-Oncogene Proteins p21(ras) / Carcinoma, Pancreatic Ductal / Carcinogenesis Limits: Animals / Humans Language: En Journal: Genes Dev Journal subject: BIOLOGIA MOLECULAR Year: 2019 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pancreatic Neoplasms / Transcription Factors / Proto-Oncogene Proteins p21(ras) / Carcinoma, Pancreatic Ductal / Carcinogenesis Limits: Animals / Humans Language: En Journal: Genes Dev Journal subject: BIOLOGIA MOLECULAR Year: 2019 Document type: Article Affiliation country: United States