Arid1a restrains Kras-dependent changes in acinar cell identity
Mutations in members of the SWI/SNF chromatin remodeling family are common events in cancer, but the mechanisms whereby disruption of SWI/SNF components alters tumorigenesis remain poorly understood. To model the effect of loss of function mutations in the SWI/SNF subunit Arid1a in pancreatic ductal...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-07-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/35216 |
| _version_ | 1811181040487628800 |
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| author | Geulah Livshits Direna Alonso-Curbelo John P Morris IV Richard Koche Michael Saborowski John Erby Wilkinson Scott W Lowe |
| author_facet | Geulah Livshits Direna Alonso-Curbelo John P Morris IV Richard Koche Michael Saborowski John Erby Wilkinson Scott W Lowe |
| author_sort | Geulah Livshits |
| collection | DOAJ |
| description | Mutations in members of the SWI/SNF chromatin remodeling family are common events in cancer, but the mechanisms whereby disruption of SWI/SNF components alters tumorigenesis remain poorly understood. To model the effect of loss of function mutations in the SWI/SNF subunit Arid1a in pancreatic ductal adenocarcinoma (PDAC) initiation, we directed shRNA triggered, inducible and reversible suppression of Arid1a to the mouse pancreas in the setting of oncogenic KrasG12D. Arid1a cooperates with Kras in the adult pancreas as postnatal silencing of Arid1a following sustained KrasG12D expression induces rapid and irreversible reprogramming of acinar cells into mucinous PDAC precursor lesions. In contrast, Arid1a silencing during embryogenesis, concurrent with KrasG12D activation, leads to retention of acinar cell fate. Together, our results demonstrate Arid1a as a critical modulator of Kras-dependent changes in acinar cell identity, and underscore an unanticipated influence of timing and genetic context on the effects of SWI/SNF complex alterations in epithelial tumorigenesis. |
| first_indexed | 2024-04-11T09:12:48Z |
| format | Article |
| id | doaj.art-8a4173c268444a4d9d05ccf1dabaeb72 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:12:48Z |
| publishDate | 2018-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8a4173c268444a4d9d05ccf1dabaeb722022-12-22T04:32:27ZengeLife Sciences Publications LtdeLife2050-084X2018-07-01710.7554/eLife.35216Arid1a restrains Kras-dependent changes in acinar cell identityGeulah Livshits0https://orcid.org/0000-0002-3835-7377Direna Alonso-Curbelo1https://orcid.org/0000-0001-6674-3059John P Morris IV2Richard Koche3https://orcid.org/0000-0002-6820-5083Michael Saborowski4John Erby Wilkinson5Scott W Lowe6https://orcid.org/0000-0002-5284-9650Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United StatesDepartment of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United StatesDepartment of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United StatesCenter of Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United StatesDepartment of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, GermanyDepartment of Pathology, University of Michigan School of Medicine, Ann Arbor, United StatesDepartment of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States; Howard Hughes Medical Institute, New York, United StatesMutations in members of the SWI/SNF chromatin remodeling family are common events in cancer, but the mechanisms whereby disruption of SWI/SNF components alters tumorigenesis remain poorly understood. To model the effect of loss of function mutations in the SWI/SNF subunit Arid1a in pancreatic ductal adenocarcinoma (PDAC) initiation, we directed shRNA triggered, inducible and reversible suppression of Arid1a to the mouse pancreas in the setting of oncogenic KrasG12D. Arid1a cooperates with Kras in the adult pancreas as postnatal silencing of Arid1a following sustained KrasG12D expression induces rapid and irreversible reprogramming of acinar cells into mucinous PDAC precursor lesions. In contrast, Arid1a silencing during embryogenesis, concurrent with KrasG12D activation, leads to retention of acinar cell fate. Together, our results demonstrate Arid1a as a critical modulator of Kras-dependent changes in acinar cell identity, and underscore an unanticipated influence of timing and genetic context on the effects of SWI/SNF complex alterations in epithelial tumorigenesis.https://elifesciences.org/articles/35216pancreas cancerSWI/SNFacinar cellmouse modelRNAiplasticity |
| spellingShingle | Geulah Livshits Direna Alonso-Curbelo John P Morris IV Richard Koche Michael Saborowski John Erby Wilkinson Scott W Lowe Arid1a restrains Kras-dependent changes in acinar cell identity eLife pancreas cancer SWI/SNF acinar cell mouse model RNAi plasticity |
| title | Arid1a restrains Kras-dependent changes in acinar cell identity |
| title_full | Arid1a restrains Kras-dependent changes in acinar cell identity |
| title_fullStr | Arid1a restrains Kras-dependent changes in acinar cell identity |
| title_full_unstemmed | Arid1a restrains Kras-dependent changes in acinar cell identity |
| title_short | Arid1a restrains Kras-dependent changes in acinar cell identity |
| title_sort | arid1a restrains kras dependent changes in acinar cell identity |
| topic | pancreas cancer SWI/SNF acinar cell mouse model RNAi plasticity |
| url | https://elifesciences.org/articles/35216 |
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