The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male MiceSummary
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 mutation...
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X18301255 |
| _version_ | 1818543188687716352 |
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| author | Claire C. Young Ryan M. Baker Christopher J. Howlett Todd Hryciw Joshua E. Herman Douglas Higgs Richard Gibbons Howard Crawford Arthur Brown Christopher L. Pin |
| author_facet | Claire C. Young Ryan M. Baker Christopher J. Howlett Todd Hryciw Joshua E. Herman Douglas Higgs Richard Gibbons Howard Crawford Arthur Brown Christopher L. Pin |
| author_sort | Claire C. Young |
| collection | DOAJ |
| description | 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 (KRASG12D). 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: Epigenetics, Pancreatic Ductal Adenocarcinoma, MIST1, SOX9 |
| first_indexed | 2024-12-11T22:32:04Z |
| format | Article |
| id | doaj.art-813dd9322f774f379dfe629c8aefcad1 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-11T22:32:04Z |
| publishDate | 2019-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-813dd9322f774f379dfe629c8aefcad12022-12-22T00:48:05ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2019-01-017193113The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male MiceSummaryClaire C. Young0Ryan M. Baker1Christopher J. Howlett2Todd Hryciw3Joshua E. Herman4Douglas Higgs5Richard Gibbons6Howard Crawford7Arthur Brown8Christopher L. Pin9Department 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, CanadaDepartment of Paediatrics, University of Western Ontario, London, Ontario, Canada; Children’s Health Research Institute, London, Ontario, CanadaDepartment of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, CanadaDepartment of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada; Robarts Research Institute, London, Ontario, CanadaRobarts Research Institute, London, Ontario, CanadaMRC Molecular Haematology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United KingdomMRC Molecular Haematology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United KingdomMolecular & Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MichiganDepartment 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, CanadaDepartment 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; Correspondence Address correspondence to: Christopher Pin, PhD, Department of Paediatrics, University of Western Ontario, Children’s Health Research Institute, 5th Floor, Victoria Research Laboratories, London, Ontario, Canada N6C 2V5. fax: (519) 685-8186.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 (KRASG12D). 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: Epigenetics, Pancreatic Ductal Adenocarcinoma, MIST1, SOX9http://www.sciencedirect.com/science/article/pii/S2352345X18301255 |
| spellingShingle | Claire C. Young Ryan M. Baker Christopher J. Howlett Todd Hryciw Joshua E. Herman Douglas Higgs Richard Gibbons Howard Crawford Arthur Brown Christopher L. Pin The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male MiceSummary Cellular and Molecular Gastroenterology and Hepatology |
| title | The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male MiceSummary |
| title_full | The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male MiceSummary |
| title_fullStr | The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male MiceSummary |
| title_full_unstemmed | The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male MiceSummary |
| title_short | The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male MiceSummary |
| title_sort | loss of atrx increases susceptibility to pancreatic injury and oncogenic kras in female but not male micesummary |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X18301255 |
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