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Cell Mol Gastroenterol Hepatol. 2018 Sep 14;7(1):93-113. doi: 10.1016/j.jcmgh.2018.09.004. eCollection 2019.

The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male Mice.

Author information

1
Department of Paediatrics, University of Western Ontario, London, Ontario, Canada; Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada; Department of Oncology, University of Western Ontario, London, Ontario, Canada; Children's Health Research Institute, London, Ontario, Canada.
2
Department of Paediatrics, University of Western Ontario, London, Ontario, Canada; Children's Health Research Institute, London, Ontario, Canada.
3
Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, Canada.
4
Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada; Robarts Research Institute, London, Ontario, Canada.
5
Robarts Research Institute, London, Ontario, Canada.
6
MRC Molecular Haematology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom.
7
Molecular & Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, Michigan.
8
Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada; Robarts Research Institute, London, Ontario, Canada; Children's Health Research Institute, London, Ontario, Canada.
9
Department of Paediatrics, University of Western Ontario, London, Ontario, Canada; Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada; Department of Oncology, University of Western Ontario, London, Ontario, Canada; Children's Health Research Institute, London, Ontario, Canada. Electronic address: cpin@uwo.ca.

Abstract

Background:

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in North America, accounting for >30,000 deaths annually. Although somatic activating mutations in KRAS appear in 97% of PDAC patients, additional factors are required to initiate PDAC. Because mutations in genes encoding chromatin remodelling proteins have been implicated in KRAS-mediated PDAC, we investigated whether loss of chromatin remodeler ɑ-thalassemia, mental-retardation, X-linked (ATRX) affects oncogenic KRAS's ability to promote PDAC. ATRX affects DNA replication, repair, and gene expression and is implicated in other cancers including glioblastomas and pancreatic neuroendocrine tumors. The hypothesis was that deletion of Atrx in pancreatic acinar cells will increase susceptibility to injury and oncogenic KRAS.

Methods:

Mice allowing conditional loss of Atrx within pancreatic acinar cells were examined after induction of recurrent cerulein-induced pancreatitis or oncogenic KRAS (KRAS G12D ). Histologic, biochemical, and molecular analysis examined pancreatic pathologies up to 2 months after induction of Atrx deletion.

Results:

Mice lacking Atrx showed more progressive damage, inflammation, and acinar-to-duct cell metaplasia in response to injury relative to wild-type mice. In combination with KRASG12D, Atrx-deficient acinar cells showed increased fibrosis, inflammation, progression to acinar-to-duct cell metaplasia, and pre-cancerous lesions relative to mice expressing only KRASG12D. This sensitivity appears only in female mice, mimicking a significant prevalence of ATRX mutations in human female PDAC patients.

Conclusions:

Our results indicate the absence of ATRX increases sensitivity to injury and oncogenic KRAS only in female mice. This is an instance of a sex-specific mutation that enhances oncogenic KRAS's ability to promote pancreatic intraepithelial lesion formation.

KEYWORDS:

ADM, acinar-to-duct cell metaplasia; ANOVA, analysis of variance; ATRX, ɑ-thalassemia, mental-retardation, X-linked; CIP, cerulein induced pancreatitis; CPA, carboxypeptidase; DAXX, death associated protein 6; EZH2, Enhancer of Zeste Homologue 2, MKA, Mist1creERT/+KrasLSL-G12D/+AtrxflΔ18; Epigenetics; MIST1; PDAC, pancreatic ductal adenocarcinoma; PanIN, pancreatic intraepithelial lesion; Pancreatic Ductal Adenocarcinoma; SOX9; WT, wild-type; ds, double stranded

PMID:
30510993
PMCID:
PMC6260375
DOI:
10.1016/j.jcmgh.2018.09.004
[Indexed for MEDLINE]
Free PMC Article

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