MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer Cells In Vitro and In Vivo
Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with a very poor prognosis. At the same time, its incidence is on the rise, and PDAC is expected to become the second leading cause of cancer-related death by 2030. Despite extensive work on new therapeutic approaches, the median...
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| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-01-01
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| Series: | Stem Cells International |
| Online Access: | http://dx.doi.org/10.1155/2019/8475389 |
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| author | Karolin Walter Kanishka Tiwary Marija Trajkovic-Arsic Ana Hidalgo-Sastre Laura Dierichs Sven T. Liffers Jiangning Gu Johann Gout Lucas-Alexander Schulte Jan Münch Thomas Seufferlein Bruno Sainz Jens T. Siveke Eva Rodriguez-Aznar Patrick C. Hermann |
| author_facet | Karolin Walter Kanishka Tiwary Marija Trajkovic-Arsic Ana Hidalgo-Sastre Laura Dierichs Sven T. Liffers Jiangning Gu Johann Gout Lucas-Alexander Schulte Jan Münch Thomas Seufferlein Bruno Sainz Jens T. Siveke Eva Rodriguez-Aznar Patrick C. Hermann |
| author_sort | Karolin Walter |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with a very poor prognosis. At the same time, its incidence is on the rise, and PDAC is expected to become the second leading cause of cancer-related death by 2030. Despite extensive work on new therapeutic approaches, the median overall survival is only 6-12 months after diagnosis and the 5-year survival is less than 7%. While pancreatic cancer is particularly difficult to treat, patients usually succumb not to the growth of the primary tumor, but to extensive metastasis; therefore, strategies to reduce the migratory and metastatic capacity of pancreatic cancer cells merit close attention. The vast majority of pancreatic cancers harbor RAS mutations. The outstanding relevance of the RAS/MEK/ERK pathway in pancreatic cancer biology has been extensively shown previously. Due to their high dependency on Ras mutations, pancreatic cancers might be particularly sensitive to inhibitors acting downstream of Ras. Herein, we use a genetically engineered mouse model of pancreatic cancer and primary pancreatic cancer cells were derived from this model to demonstrate that small-molecule MEK inhibitors functionally abrogate cancer stem cell populations as demonstrated by reduced sphere and organoid formation capacity. Furthermore, we demonstrate that MEK inhibition suppresses TGFβ-induced epithelial-to-mesenchymal transition and migration in vitro and ultimately results in a highly significant reduction in circulating tumor cells in mice. |
| format | Article |
| id | doaj-art-ad1215332ec0444484f7cbd7da9ccd50 |
| institution | Kabale University |
| issn | 1687-966X 1687-9678 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Stem Cells International |
| spelling | doaj-art-ad1215332ec0444484f7cbd7da9ccd502025-02-03T01:11:11ZengWileyStem Cells International1687-966X1687-96782019-01-01201910.1155/2019/84753898475389MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer Cells In Vitro and In VivoKarolin Walter0Kanishka Tiwary1Marija Trajkovic-Arsic2Ana Hidalgo-Sastre3Laura Dierichs4Sven T. Liffers5Jiangning Gu6Johann Gout7Lucas-Alexander Schulte8Jan Münch9Thomas Seufferlein10Bruno Sainz11Jens T. Siveke12Eva Rodriguez-Aznar13Patrick C. Hermann14Department of Internal Medicine I, Ulm University, GermanyDepartment of Internal Medicine I, Ulm University, GermanyDivision of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, GermanyKlinik und Poliklinik für Innere Medizin II, Technical University Munich, GermanyDivision of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, GermanyDivision of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, GermanyDivision of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, GermanyDepartment of Internal Medicine I, Ulm University, GermanyDepartment of Internal Medicine I, Ulm University, GermanyInstitute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, GermanyDepartment of Internal Medicine I, Ulm University, GermanyDepartment of Biochemistry, Universidad Autónoma de Madrid (UAM), Madrid, SpainDivision of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, GermanyDepartment of Internal Medicine I, Ulm University, GermanyDepartment of Internal Medicine I, Ulm University, GermanyPancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with a very poor prognosis. At the same time, its incidence is on the rise, and PDAC is expected to become the second leading cause of cancer-related death by 2030. Despite extensive work on new therapeutic approaches, the median overall survival is only 6-12 months after diagnosis and the 5-year survival is less than 7%. While pancreatic cancer is particularly difficult to treat, patients usually succumb not to the growth of the primary tumor, but to extensive metastasis; therefore, strategies to reduce the migratory and metastatic capacity of pancreatic cancer cells merit close attention. The vast majority of pancreatic cancers harbor RAS mutations. The outstanding relevance of the RAS/MEK/ERK pathway in pancreatic cancer biology has been extensively shown previously. Due to their high dependency on Ras mutations, pancreatic cancers might be particularly sensitive to inhibitors acting downstream of Ras. Herein, we use a genetically engineered mouse model of pancreatic cancer and primary pancreatic cancer cells were derived from this model to demonstrate that small-molecule MEK inhibitors functionally abrogate cancer stem cell populations as demonstrated by reduced sphere and organoid formation capacity. Furthermore, we demonstrate that MEK inhibition suppresses TGFβ-induced epithelial-to-mesenchymal transition and migration in vitro and ultimately results in a highly significant reduction in circulating tumor cells in mice.http://dx.doi.org/10.1155/2019/8475389 |
| spellingShingle | Karolin Walter Kanishka Tiwary Marija Trajkovic-Arsic Ana Hidalgo-Sastre Laura Dierichs Sven T. Liffers Jiangning Gu Johann Gout Lucas-Alexander Schulte Jan Münch Thomas Seufferlein Bruno Sainz Jens T. Siveke Eva Rodriguez-Aznar Patrick C. Hermann MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer Cells In Vitro and In Vivo Stem Cells International |
| title | MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer Cells In Vitro and In Vivo |
| title_full | MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer Cells In Vitro and In Vivo |
| title_fullStr | MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer Cells In Vitro and In Vivo |
| title_full_unstemmed | MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer Cells In Vitro and In Vivo |
| title_short | MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer Cells In Vitro and In Vivo |
| title_sort | mek inhibition targets cancer stem cells and impedes migration of pancreatic cancer cells in vitro and in vivo |
| url | http://dx.doi.org/10.1155/2019/8475389 |
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