ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis

Lidong Wang; Huibin Yang; Andrea Zamperone; Daniel Diolaiti; Phillip L Palmbos; Ethan V Abel; Vinee Purohit; Igor Dolgalev; Andrew D Rhim; Mats Ljungman; Christina H Hadju; Christopher J Halbrook; Dafna Bar-Sagi; Marina Pasca di Magliano; Howard C Crawford; Diane M Simeone

doi:10.1101/gad.323303.118

ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis

Genes Dev. 2019 Jun 1;33(11-12):641-655. doi: 10.1101/gad.323303.118. Epub 2019 May 2.

Authors

Lidong Wang^{1

2}, Huibin Yang³, Andrea Zamperone^{1

2}, Daniel Diolaiti^{1

2}, Phillip L Palmbos⁴, Ethan V Abel⁵, Vinee Purohit^{1

2}, Igor Dolgalev², Andrew D Rhim⁶, Mats Ljungman³, Christina H Hadju⁷, Christopher J Halbrook⁵, Dafna Bar-Sagi^{2

8

9}, Marina Pasca di Magliano^{10

11}, Howard C Crawford^{4

5}, Diane M Simeone^{1

2

7}

Affiliations

¹ Department of Surgery, New York University School of Medicine, New York, New York 10016, USA.
² Perlmutter Cancer Center, NYU Langone Medical Center, New York University, New York, New York 10016, USA.
³ Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁴ Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁵ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁶ Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
⁷ Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.
⁸ Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
⁹ Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
¹⁰ Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA.
¹¹ Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.

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: SOX9; ATDC; KRAS; PanIN lesion; TRIM29; acinar-to-ductal metaplasia; pancreatic ductal adenocarcinoma; β-catenin.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acinar Cells / metabolism
Acinar Cells / pathology
Animals
Carcinogenesis*
Carcinoma in Situ / pathology
Carcinoma in Situ / physiopathology
Carcinoma, Pancreatic Ductal / pathology
Carcinoma, Pancreatic Ductal / physiopathology*
Cell Transdifferentiation
Cells, Cultured
DNA-Binding Proteins / metabolism
Down-Regulation
Gene Knockdown Techniques
Humans
Metaplasia
Mice
Mice, Transgenic
Pancreatic Ducts / metabolism
Pancreatic Ducts / pathology
Pancreatic Neoplasms / pathology
Pancreatic Neoplasms / physiopathology*
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism*
SOX9 Transcription Factor / genetics
SOX9 Transcription Factor / metabolism
Signal Transduction
Transcription Factors / genetics
Transcription Factors / metabolism
Transcription Factors / physiology*
beta Catenin / metabolism

Substances

CTNNB1 protein, human
CTNNB1 protein, mouse
DNA-Binding Proteins
SOX9 Transcription Factor
SOX9 protein, human
Sox9 protein, mouse
TRIM29 protein, human
TRIM29 protein, mouse
Transcription Factors
beta Catenin
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding