Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2020 Targeting STK11-Inactivation Induced Invasion and Harnessing ฀-Catenin - CBP/P300 Signaling as a Potential Therapeutic Option in Cutaneous Melanoma Dzung, Andreas Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-194962 Dissertation Published Version Originally published at: Dzung, Andreas. Targeting STK11-Inactivation Induced Invasion and Harnessing ฀-Catenin - CBP/P300 Signaling as a Potential Therapeutic Option in Cutaneous Melanoma. 2020, University of Zurich, Faculty of Medicine. Targeting STK11-Inactivation Induced Invasion and Harnessing -Catenin - CBP/P300 Signaling as a Potential Therapeuticβ Option in Cutaneous Melanoma Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Andreas Li-Wen Michael Dzung von Wettingen AG, Schweiz .......................................................................... Promotionskommission Prof. Dr. Med. Reinhard Dummer (Vorsitz) Prof. Dr. Mitch Levesque (Leitung der Dissertation) Prof. Dr. Lucas Pelkmans Prof. Dr. Berend Snijder Zürich, 2020 2 Melanoma - Overview This thesis is dedicated to my mother, Ruth Amacher-Dzung, who lost the battle against melanoma, and to my father, Dacfey Dzung. I feel eternally grateful for your love, guidance and for all that I have learnt from you. Thank you, for giving me the chance to grow up and to be raised in a happy and loving family environment. I will always look up to you and sincerely hope, I will be able to pass what you taught me onto the next generation. Melanoma - Overview 3 Contents I. Abstract ............................................................................................................................ 6 II. Introduction ....................................................................................................................... 7 1 Melanoma - Overview ...................................................................................................... 7 2 Epidemiology and Risk Factors ........................................................................................8 2.1 Incidence and mortality .............................................................................................8 2.2 Risk factors ...............................................................................................................8 3 Molecular Mechanisms .................................................................................................. 10 3.1 RAS-RAF-MEK-ERK MAPK-pathway ..................................................................... 11 3.2 PI3K-AKT pathway ................................................................................................ 12 3.3 Immune evasion ...................................................................................................... 13 4 Melanoma Diagnosis, Classification and Pathophysiology ............................................... 15 4.1 Initial optical examination ....................................................................................... 15 4.2 Melanoma classification .......................................................................................... 16 4.3 Melanoma staging ................................................................................................... 27 5 Melanoma Therapy ........................................................................................................ 36 5.1 Localized disease (primary tumor) treatment .......................................................... 36 5.2 Locoregional disease treatment ............................................................................... 37 5.3 Adjuvant therapy .................................................................................................... 37 5.4 Treatment of advanced metastatic disease .............................................................. 40 6 References .....................................................................................................................44 III. Projects ......................................................................................................................... 62 1 STK11 inactivation increases melanoma invasion through increased STAT3 and FAK activitation .......................................................................................................................... 62 ABSTRACT ..................................................................................................................... 63 4 Melanoma - Overview INTRODUCTION ........................................................................................................... 64 RESULTS ........................................................................................................................ 65 DISCUSSION .................................................................................................................. 70 MATERIAL AND METHODS .......................................................................................... 73 ACKNOWLEDGMENTS ................................................................................................ 80 FIGURES ........................................................................................................................ 81 REFERENCES ............................................................................................................... 90 2 Inhibition of -catenin/CBP-signaling with ICG-001 shows therapeutic potential in cutaneous melanomaβ ............................................................................................................ 94 ABSTRACT ..................................................................................................................... 95 INTRODUCTION ........................................................................................................... 96 RESULTS ........................................................................................................................98 DISCUSSION ................................................................................................................ 103 MATERIAL AND METHODS ........................................................................................ 105 ACKNOWLEDGEMENTS .............................................................................................. 110 FIGURES ........................................................................................................................ 111 REFERENCES ............................................................................................................... 117 3 Stability of SARS-CoV-2 in VTM over Time and After Freeze-Thawing ........................ 120 ABSTRACT .................................................................................................................... 121 INTRODUCTION .......................................................................................................... 122 RESULTS ...................................................................................................................... 123 DISCUSSION ................................................................................................................ 125 MATERIALS AND METHODS ...................................................................................... 127 ACKNOWLEDGMENTS ............................................................................................... 129 FIGURES ...................................................................................................................... 130 Melanoma - Overview 5 REFERENCES .............................................................................................................. 135 4 Further projects that led to publications ....................................................................... 136 Activation of the CD271 (NGFR) intracellular death domain induces apoptosis and overcomes targeted therapy resistance in melanoma (2020). Manuscript submitted to Cancer Discovery ...................................................................................................................................... 136 miR-181a decelerates proliferation in cutaneous squamous cell carcinoma by targeting the proto-oncogene KRAS (2017). PLoS One ....................................................................... 136 A Transcriptionally Inactive ATF2 Variant Drives Melanomagenesis (2016). Cell Reports ...................................................................................................................................... 136 IV. Acknowledgements ...................................................................................................... 137 6 Melanoma - Overview I. Abstract Melanoma is an aggressive skin cancer with historically poor survival due to low sensitivity to cytotoxic chemotherapy. Recently, novel therapeutic approaches, such as targeted therapy against the frequently activated mitogen-activated-protein-kinase (MAPK) pathway and immune- checkpoint inhibitor therapy have improved the prognosis of patients with metastasized melanoma. However, resistance formation or low response frequently occur. Thus, further mechanistic studies of melanoma progression and survival may eventually lead to therapeutic options. In my thesis, I assessed the role of the