ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis.,Genes & Development

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ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis.
Genes & Development ( IF 10.5 ) Pub Date : 2019-05-02 , DOI: 10.1101/gad.323303.118
Lidong Wang _{1,

2} , Huibin Yang ₃ , Andrea Zamperone _{1,

2} , Daniel Diolaiti _{1,

2} , Phillip L Palmbos ₄ , Ethan V Abel ₅ , Vinee Purohit _{1,

2} , Igor Dolgalev ₂ , Andrew D Rhim ₆ , Mats Ljungman ₃ , Christina H Hadju ₇ , Christopher J Halbrook ₅ , Dafna Bar-Sagi _{2,

8,

9} , Marina Pasca di Magliano _{10,

11} , Howard C Crawford _{4,

5} , Diane M Simeone _{1,

2,

7}

Affiliation

Department of Surgery, New York University School of Medicine, New York, New York 10016, USA.
Perlmutter Cancer Center, NYU Langone Medical Center, New York University, New York, New York 10016, USA.
Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA.
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.

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.

中文翻译：

ATDC是启动KRAS诱导的胰腺肿瘤发生所必需的。

胰腺腺癌（PDA）是一种由致癌性KRAS驱动的侵袭性疾病，其特征在于晚期诊断和治疗耐药性。在这里，我们显示共济失调-毛细血管扩张组D-补体（Atdc）基因的缺失，其人类同源物在大多数胰腺腺癌中上调，在致癌性KRAS的背景下完全阻止了PDA的发展。ATDC是KRAS驱动的腺导管上皮化生（ADM）及其进展为胰腺上皮内瘤变（PanIN）所必需的。结果，保护了缺少ATDC的小鼠免于发展PDA。从机制上讲，我们显示ATDC通过激活β-catenin信号传导和随后的SOX9上调来促进ADM向PanIN的发展。

更新日期：2019-11-01

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