Dataset Information

MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer Cells In Vitro and In Vivo.

ABSTRACT: 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 TGF?-induced epithelial-to-mesenchymal transition and migration in vitro and ultimately results in a highly significant reduction in circulating tumor cells in mice.

SUBMITTER: Walter K

PROVIDER: S-EPMC6589314 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer Cells <i>In Vitro</i> and <i>In Vivo</i>.

Walter Karolin K Tiwary Kanishka K Trajkovic-Arsic Marija M Hidalgo-Sastre Ana A Dierichs Laura L Liffers Sven T ST Gu Jiangning J Gout Johann J Schulte Lucas-Alexander LA Münch Jan J Seufferlein Thomas T Sainz Bruno B Siveke Jens T JT Rodriguez-Aznar Eva E Hermann Patrick C PC

Stem cells international 20190602

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 ...[more]

PMID: 31281387

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Project description:Pancreatic cancer, mostly pancreatic ductal adenocarcinoma (PDAC), is one of the most lethal cancer types, with an estimated 44,330 death in 2018 in the US alone. While targeted therapies and immune checkpoint inhibitors have significantly improved treatment options for patients with lung cancer and renal cell carcinomas, little progress has been made in pancreatic cancer, with a dismal 5-year survival rate currently at ~8%. Upon diagnosis, the majority of pancreatic cancer cases (~80%) are already metastatic. Thus, identifying ways to reduce pancreatic cancer metastasis is an unmet medical need. Furthermore, pancreatic cancer is notorious resistant to chemotherapy. While Kirsten RAt Sarcoma virus oncogene (K-RAS) mutation is the major driver for pancreatic cancer, specific inhibition of RAS signaling has been very challenging, and combination therapy is thought to be promising. In this study, we report that combination of hedgehog (Hh) and Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase (MEK) signaling inhibitors reduces pancreatic cancer metastasis in mouse models. In mouse models of pancreatic cancer metastasis using human pancreatic cancer cells, we found that Hh target gene Gli1 is up-regulated during pancreatic cancer metastasis. Specific inhibition of smoothened signaling significantly altered the gene expression profile of the tumor microenvironment but had no significant effects on cancer metastasis. By combining Hh signaling inhibitor BMS833923 with RAS downstream MEK signaling inhibitor AZD6244, we observed reduced number of metastatic nodules in several mouse models for pancreatic cancer metastasis. These two inhibitors also decreased cell proliferation significantly and reduced CD45? cells (particularly Ly6G?CD11b? cells). We demonstrated that depleting Ly6G? CD11b? cells is sufficient to reduce cancer cell proliferation and the number of metastatic nodules. In vitro, Ly6G? CD11b? cells can stimulate cancer cell proliferation, and this effect is sensitive to MEK and Hh inhibition. Our studies may help design novel therapeutic strategies to mitigate pancreatic cancer metastasis.

Dataset Information

MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer Cells In Vitro and In Vivo.

Publications

MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer Cells <i>In Vitro</i> and <i>In Vivo</i>.

Similar Datasets

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