Fbxw7 Deletion Accelerates KrasG12D-Driven Pancreatic Tumorigenesis via Yap Accumulation
Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-11-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558616301464 |
| _version_ | 1819112429949288448 |
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| author | Qiang Zhang Yaqing Zhang Joshua D. Parsels Ines Lohse Theodore S. Lawrence Marina Pasca di Magliano Yi Sun Meredith A. Morgan |
| author_facet | Qiang Zhang Yaqing Zhang Joshua D. Parsels Ines Lohse Theodore S. Lawrence Marina Pasca di Magliano Yi Sun Meredith A. Morgan |
| author_sort | Qiang Zhang |
| collection | DOAJ |
| description | Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in pancreatic tumorigenesis, we generated P48-Cre;LSL-KrasG12D;Fbxw7fl/fl (KFCfl/fl) compound mice. We found that KFCfl/fl mice displayed accelerated tumorigenesis: all mice succumbed to pancreatic ductal adenocarcinoma (PDA) by 40 days of age, with PDA onset occurring by 2 weeks of age. PDA in KFCfl/fl mice was preceded by earlier onset of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions, and associated with chromosomal instability and the accumulation of Fbxw7 substrates Yes-associated protein (Yap), c-Myc, and Notch. Using KFCfl/fl and FBXW7-deficient human pancreatic cancer cells, we found that Yap silencing attenuated growth promotion by Fbxw7 deletion. Our data demonstrate that Fbxw7 is a potent suppressor of KrasG12D-induced pancreatic tumorigenesis due, at least in part, to negative regulation of Yap. |
| first_indexed | 2024-12-22T04:13:23Z |
| format | Article |
| id | doaj.art-f0b258a5d25a477bbda0001384e57cba |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-22T04:13:23Z |
| publishDate | 2016-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-f0b258a5d25a477bbda0001384e57cba2022-12-21T18:39:28ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022016-11-01181166667310.1016/j.neo.2016.08.009Fbxw7 Deletion Accelerates KrasG12D-Driven Pancreatic Tumorigenesis via Yap AccumulationQiang Zhang0Yaqing Zhang1Joshua D. Parsels2Ines Lohse3Theodore S. Lawrence4Marina Pasca di Magliano5Yi Sun6Meredith A. Morgan7Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USAPancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in pancreatic tumorigenesis, we generated P48-Cre;LSL-KrasG12D;Fbxw7fl/fl (KFCfl/fl) compound mice. We found that KFCfl/fl mice displayed accelerated tumorigenesis: all mice succumbed to pancreatic ductal adenocarcinoma (PDA) by 40 days of age, with PDA onset occurring by 2 weeks of age. PDA in KFCfl/fl mice was preceded by earlier onset of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions, and associated with chromosomal instability and the accumulation of Fbxw7 substrates Yes-associated protein (Yap), c-Myc, and Notch. Using KFCfl/fl and FBXW7-deficient human pancreatic cancer cells, we found that Yap silencing attenuated growth promotion by Fbxw7 deletion. Our data demonstrate that Fbxw7 is a potent suppressor of KrasG12D-induced pancreatic tumorigenesis due, at least in part, to negative regulation of Yap.http://www.sciencedirect.com/science/article/pii/S1476558616301464 |
| spellingShingle | Qiang Zhang Yaqing Zhang Joshua D. Parsels Ines Lohse Theodore S. Lawrence Marina Pasca di Magliano Yi Sun Meredith A. Morgan Fbxw7 Deletion Accelerates KrasG12D-Driven Pancreatic Tumorigenesis via Yap Accumulation Neoplasia: An International Journal for Oncology Research |
| title | Fbxw7 Deletion Accelerates KrasG12D-Driven Pancreatic Tumorigenesis via Yap Accumulation |
| title_full | Fbxw7 Deletion Accelerates KrasG12D-Driven Pancreatic Tumorigenesis via Yap Accumulation |
| title_fullStr | Fbxw7 Deletion Accelerates KrasG12D-Driven Pancreatic Tumorigenesis via Yap Accumulation |
| title_full_unstemmed | Fbxw7 Deletion Accelerates KrasG12D-Driven Pancreatic Tumorigenesis via Yap Accumulation |
| title_short | Fbxw7 Deletion Accelerates KrasG12D-Driven Pancreatic Tumorigenesis via Yap Accumulation |
| title_sort | fbxw7 deletion accelerates krasg12d driven pancreatic tumorigenesis via yap accumulation |
| url | http://www.sciencedirect.com/science/article/pii/S1476558616301464 |
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