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The New Role of TGF-Β Superfamily Signaling in Melanoma

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The New Role of TGF-Β Superfamily Signaling in Melanoma Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2017 The new role of TGF-฀ superfamily signaling in melanoma Tuncer, Eylül Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-148195 Dissertation Published Version Originally published at: Tuncer, Eylül. The new role of TGF-฀ superfamily signaling in melanoma. 2017, University of Zurich, Faculty of Science. The New Role of TGF-β Superfamily Signaling in Melanoma Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Eylül Tuncer Aus der Türkei Promotionskommission Prof. Dr. Lukas Sommer (Leitung und Vorsitz der Dissertation) Prof. Dr. med. Onur Boyman Prof. Dr. med. Markus Manz Prof. Dr. Burkhard Becher Zürich, 2017 Table of Contents Table of Contents ......................................................................................................... 2 1. Summary .................................................................................................................. 5 2. Zusammenfassung ..................................................................................................... 6 3. Introduction .............................................................................................................. 8 3.1 Definition and Epidemiology of Cutaneous Melanoma ................................................ 8 3.2 Clinical features ...................................................................................................... 9 3.2.1 The Clinical Presentation and Morphology ............................................................ 11 3.3 Pathological features and staging ............................................................................ 11 3.3.1 Clark’s level of invasion and Breslow’s thickness .................................................. 11 3.3.3 TNM staging system ........................................................................................... 12 3.4 Pathogenesis of cutaneous melanoma ...................................................................... 13 3.4.1 Chronically sun damaged melanoma vs. non-sun damaged melanoma ...................... 14 3.4.2 Melanoma Progression ........................................................................................ 15 3.4.3.1 BRAF Subtype ................................................................................................ 18 3.4.3.2 RAS Subtype ................................................................................................... 19 3.4.3.3 NF1 Subtype ................................................................................................... 19 3.4.3.4 Triple Wild-Type Subtype ................................................................................ 19 3.4.3.5 Genes involved in familial melanoma ................................................................. 20 3.4.3.5.1 High penetrance genes ................................................................................... 20 3.4.3.5.1 Low penetrance genes .................................................................................... 21 3.4.4 Molecular alterations in signal pathways of melanoma ........................................... 22 3.4.4.1 PTEN signaling ............................................................................................... 22 3.4.5.2 The RAS/RAF/MEK/ERK pathway ................................................................... 24 3.4.5.3 WNT Signaling ................................................................................................ 25 3.4.5.4 TGF-β Signaling and deciphering the molecular components ................................ 26 3.4.5.4.1 SMAD Proteins ............................................................................................. 28 3.5 TGF-β Superfamily ligands and cancer .................................................................... 30 3.5.1 TGF-β isoforms .................................................................................................. 30 3.5.2 TGF-β’s tumor suppressor role ............................................................................. 32 3.5.3 TGF-β’s tumor promoter role ............................................................................... 32 2 3.5.2 Activin .............................................................................................................. 35 3.5.3 Activins in melanoma.......................................................................................... 35 3.5.4. NODAL ............................................................................................................ 36 3.5.5 NODAL signaling in melanoma ........................................................................... 37 3.5.6. BMPs ............................................................................................................... 38 3.5.7 BMPs in melanoma ............................................................................................. 39 3.5.8 Negative growth regulators and tumorigenesis ....................................................... 40 3.6 Phenotype Switching model ................................................................................... 40 3.6.1 MITF and AXL .................................................................................................. 42 4. Approaches to investigating the roles of TGF-β signaling in melanoma ........................ 46 5. My Contribution to the projects ................................................................................ 47 6. Results ................................................................................................................... 48 6.1 Journal of Clinical Investigations Under Revision 2017 ............................................. 48 6.1 Abstract ................................................................................................................ 49 6.1 Introduction .......................................................................................................... 49 6.1.1 Conditional Smad4 deletion in a genetic mouse model of melanoma prevents tumorigenesis by reducing tumor cell proliferation ......................................................... 52 6.1.3 BMP7 signaling promotes melanoma cell growth ................................................... 58 6.1.7 Reduced Smad7 expression promotes massive metastatic spread of melanoma in vivo77 7. Methods ................................................................................................................. 82 7.1 Mice .................................................................................................................... 82 7.2 Immunofluorescent on cells .................................................................................... 82 7.3 Administration of tamoxifen and analysis of mice ..................................................... 83 7.4 Quantification of skin melanomas and metastases ..................................................... 83 7.5 Histologic analysis and immunohistochemistry ......................................................... 84 7.6 Analysis of proliferation and apoptosis .................................................................... 85 7.7 Correlation Analysis .............................................................................................. 85 7.8 Cell culture, Cell Cycle Analysis and Ligand Treatments ........................................... 86 7.8 RNA Interference .................................................................................................. 86 7.9 Quantitative RT-PCR and RNA Sequencing ............................................................. 87 7.9 Protein Isolation and Western Blotting ..................................................................... 87 7.10 TCGA Analysis ................................................................................................... 88 7.11 Attachment Assay Using Fibronectin-Coated Plates ................................................ 88 3 7.12 Supplementary Tables .......................................................................................... 89 7.12.1 Supplementary Table 1. GO Process ................................................................... 89 7.12.3 Supplementary Table 3 Overlapping genes with MITF and AXL Program .............. 92 7.12.4 Supplementary Table 4. Mouse Genotyping Primers ............................................. 93 7.12.5 Supplementary Table 5. Antibodies .................................................................... 93 7.12.6 Supplementary Table 6. siRNAs and Primer sequences ......................................... 94 7.12.7 Supplementary Table 7. Ligand information ........................................................ 95 8. Discussion .............................................................................................................. 96 8.1 Current Model ..................................................................................................... 100 9. Curriculum Vitae .................................................................................................. 101 10. Acknowledgments .............................................................................................. 104 4 1. Summary Cutaneous melanoma is the most deadly skin cancer with a yearly rising incidence. The
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