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Cited by 16Pancreatic and Hepatic Oncology ResearchCancer Cells and MetastasisProtein Kinase Regulation and GTPase Signaling

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

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Walter, Karolin, Tiwary, Kanishka, Trajkovic-Arsic, Marija, Hidalgo-Sastre, Ana, Dierichs, Laura, Liffers, Sven T., Gu, Jiangning, Gout, Johann +7 more·2019·Stem Cells International
DOI 10.1155/2019/8475389PMC PMC6589314
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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 β-induced epithelial-to-mesenchymal transition and migration in vitro and ultimately results in a highly significant reduction in circulating tumor cells in mice.

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  • Specific recombination in epithelial cells of the pancreas was confirmed by immunohistochemical stainings for tdRFP.

    “Specific recombination in epithelial cells of the pancreas was confirmed by immunohistochemical stainings for tdRFP in Ptf1aCre/+ [35] x LSL-tdRFPKI/KI [55, 56] mice (Additional file 1: Fig. S3d) [56].”

    From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [56]

    Methods §2.1 describes mice carrying Ptf1a-driven Cre and an LSL-tdRFP reporter, and Results §3.3 says Ptf1a-mediated RFP expression reports pancreatic and pancreas-derived cells. Neither passage reports immunohistochemical staining for tdRFP or says that staining confirmed recombination specifically in pancreatic epithelial cells. Page numbers were not available in our copy. (LLM, conf=0.78)

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Authors
Walter, K., Tiwary, K., Trajkovic-Arsic, M., Hidalgo-Sastre, A., Dierichs, L., Liffers, S. T., Gu, J., Gout, J., Schulte, L.-A., Münch, J., Seufferlein, T., Sainz, B., Siveke, J. T., Rodriguez-Aznar, E., & Hermann, P. C.
Affiliations
  • Universität Ulm (DE)
  • Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany
  • Klinik und Poliklinik für Innere Medizin II, Technical University Munich, Germany
  • German Cancer Research Center (DE)
  • University Hospital Ulm (DE)
  • Department of Biochemistry, Universidad Autónoma de Madrid (UAM), Madrid, Spain
  • Department of Internal Medicine I, Ulm University, Germany
Corresponding author
Hermann, Patrick C.
ORCID
Venue
Stem Cells International
Publisher
Wiley
Published
2019-06-02
Volume
2019
Pages
1-11
ISSN
  • 1687-966X (ISSN-L)
  • 1687-9678
DOI
10.1155/2019/8475389
PMC
PMC6589314
OpenAlex
W2947644940
Cited by
16
References
1
Citations by year
2026: 1 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 2
FWCI
1.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cells International (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
  • Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders
  • Fundación Asociación Española Contra el Cáncer (GC16173694BARB, KFO337/SI 1549/3-1, 316249678–SFB 1279, 602783, M65.1)
  • Ministerio de Economía y Competitividad (GC16173694BARB, KFO337/SI 1549/3-1, 316249678–SFB 1279, 602783, M65.1)
  • Deutsche Forschungsgemeinschaft (GC16173694BARB, KFO337/SI 1549/3-1, 316249678–SFB 1279, 602783, M65.1)
  • German Cancer Consortium (GC16173694BARB, KFO337/SI 1549/3-1, 316249678–SFB 1279, 602783, M65.1)
  • Seventh Framework Programme (GC16173694BARB, KFO337/SI 1549/3-1, 316249678–SFB 1279, 602783, M65.1)
  • Hector Foundation Cancer Research (GC16173694BARB, KFO337/SI 1549/3-1, 316249678–SFB 1279, 602783, M65.1)
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
MEK inhibitors, pancreatic ductal adenocarcinoma, cancer stem cells, cell migration, metastasis, Ras/MEK/ERK pathway, RAS mutations, epithelial-mesenchymal transition, TGF-beta, circulating tumor cells, organoids, genetically engineered mouse models

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