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The Function of Wnt/Beta-Catenin Signaling in Ewing Sarcoma and Its Contribution to Pathogenesis

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The Function of Wnt/Beta-Catenin Signaling in Ewing Sarcoma and Its Contribution to Pathogenesis The function of Wnt/beta-catenin signaling in Ewing sarcoma and its contribution to pathogenesis by Elisabeth Anne Pedersen A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Molecular and Cellular Pathology) The University of Michigan 2016 Doctoral Committee: Associate Professor Elizabeth R. Lawlor, Chair Professor Kenneth Cadigan Professor Colin Duckett Professor Eric R. Fearon Associate Professor Zaneta Nikolovska-Coleska Professor Russell S. Taichman © Elisabeth Anne Pedersen All Rights Reserved 2016 DEDICATION Dedicated to the patients for whom this work is intended, and to my husband Chase, who spent many evenings in the lab too. ii ACKNOWLEDGEMENTS I would like to thank a the current members of the Lawlor lab for their scientific input technical assistance, and friendship, including Kelly Bailey, Ally Hawkins, Laurie Svoboda, Sudha Sud, Raelene Van Noord, and of course Beth Lawlor. Further thank you to former members Chris Scannell, Merlin Airik, Ashley Harris, Natashay Bailey, Katherine Ryland, Melanie Krook, and Jack Mosher. I am extremely grateful to temporary students Jay Read, Jenny Tran, Morgan Penny, and Jane Song, who all helped collect and interpret data in this dissertation. I would also like to acknowledge Raji Menon, Dafydd Thomas, Rashmi Chugh, Pingping Qu, Hongwei Wang, Antje Hoering, who all helped collect and interpret patient information and data for these studies. Many additional thanks to the Medical Scientist Training Program members including Ron Koenig, Ellen Elkin, Laurie Koivupalo, and Hilkka Ketola, as well as Laura Labut and Zaneta Niklovska-Coleska, and Nick Lukacs from Molecular and Cellular Pathology. Thank you for helping me to get through the years smoothly. I am lucky to have been a part of such great programs. An especially large thank you goes to my committee for always challenging me, providing me with guidance and scientific input. Thank you for meeting with me formally and individually – I have delighted in getting to know you all, and learn from you. Zaneta Nikolovska-Coleska has been especially supportive, and I would also like to thank her for being such a delightful and wonderful role model. A huge shout-out goes to Russ Taichman for his support and mentorship over the last ten (!) years. Thank you for inspiring me and teaching me more than I can express here. A special note of thanks to my mentor Beth Lawlor – I will be eternally grateful for the opportunity to work in your lab and learn from you, and always will look fondly on these years. The immeasurable amount of scientific and career skills I have learned will iii travel with me always, and I cannot thank you enough. On top of all of it all, it has really been so much fun. Thank you for everything! I would also like to thank my parents Annemarie and Brian Pedersen, whose contribution to this process cannot be described, as well as my twin brother Nick and little sister Christina, who have been my best friends for life. Thank you to my parents- in-law, Chuck and Cindy Schuler, as well as Andrew and Claire Schuler, for not only their unending support but for always providing me with a beautiful place to rest. Thank you to my non-science friends Samantha Krench, Emily Baxter, and Anna James, who have been like family throughout these years. Finally, a special thank you to my husband Chase Schuler. Thank you for listening, discussing, reading, and debating everything about this process through the years. Thank you for keeping me company in the lab during the odd hours. No, opening the freezer door for me will not get you authorship on my papers. Thank you for supporting me and loving me through everything. iv TABLE OF CONTENTS Dedication ........................................................................................................................ii Acknowledgements ......................................................................................................... iii List of FIgures ............................................................................................................... viii List of Tables ................................................................................................................... x List of Abbreviations ........................................................................................................xi Abstract ......................................................................................................................... xiii Chapter 1: Introduction .................................................................................................... 1 Rationale ..................................................................................................................... 1 Ewing sarcoma overview ............................................................................................. 2 Molecular genetics ................................................................................................... 3 Developmental origins .............................................................................................. 5 Mechanisms that promote aggressive disease ........................................................ 6 Wnt/beta-catenin signaling .......................................................................................... 7 Mechanism of signaling ............................................................................................ 8 Regulation of Wnt/beta-catenin signaling ................................................................. 9 Functions of Wnt/beta-catenin signaling in development and homeostasis ........... 10 Wnt/beta-catenin signaling in cancer ..................................................................... 12 Wnt signaling in sarcomas ..................................................................................... 13 Wnt/beta-catenin signaling in Ewing sarcoma ........................................................ 14 Non-canonical Wnt signaling in Ewing sarcoma .................................................... 17 Summary ................................................................................................................... 18 Chapter 2: Activation of Wnt/Beta-Catenin Signaling in Tumor Cell Subpopulations Promotes Ewing Sarcoma Progression by Antagonizing EWS/ETS Fusions ................ 19 Abstract ..................................................................................................................... 19 Introduction ................................................................................................................ 21 Results ....................................................................................................................... 23 v The LGR-Wnt/beta-catenin signaling axis is heterogeneously active in Ewing sarcoma tumors in vivo .......................................................................................... 23 The response of Ewing sarcoma cells to Wnt3a signaling in vitro is heterogeneous ............................................................................................................................... 26 RNA profiling identifies novel targets of canonical Wnt-signaling in Ewing sarcoma cells ........................................................................................................................ 33 Activation of Wnt/beta-catenin antagonizes EWS/ETS-dependent transcription .... 37 Wnt/beta-catenin signaling promotes cytoskeleton changes and a migratory and metastatic phenotype ............................................................................................. 44 Ewing sarcoma tumors with evidence of robust Wnt/beta-catenin activation are associated with a worse clinical outcome ............................................................... 50 Discussion ................................................................................................................. 54 Experimental Procedures .......................................................................................... 61 Chapter 3: Tenascin C is regulated by Wnt/beta-catenin signaling and promotes ewing sarcoma metastasis ...................................................................................................... 70 Abstract ..................................................................................................................... 70 Introduction ................................................................................................................ 72 Results ....................................................................................................................... 74 TNC is expressed by Ewing sarcoma cells ............................................................ 74 TNC is regulated by Wnt/beta-catenin signaling in Ewing sarcoma ....................... 75 TNC is variably regulated by Wnt/beta-catenin in stem cells and other tumors ..... 78 TNC promotes Ewing sarcoma cell migration and tumorigenicity in vivo ............... 81 TNC promotes in vivo metastasis of Ewing sarcoma cells ..................................... 83 Discussion ................................................................................................................. 87 Experimental Procedures .......................................................................................... 91 Chapter 4: Prognostic and Therapeutic Significance of Wnt/beta-catenin signaling in the context of the ewing sarcoma microenvironment .........................................................
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