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The Molecular Role of Non-Canonical Notch Signaling Via Deltex-1 in High Grade Glioma

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The Molecular Role of Non-Canonical Notch Signaling Via Deltex-1 in High Grade Glioma THE MOLECULAR ROLE OF NON-CANONICAL NOTCH SIGNALING VIA DELTEX-1 IN HIGH GRADE GLIOMA Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Roland Martin Huber aus Siegershausen TG Basel, 2011 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von: Prof. Dr. Markus A. Rüegg (Fakultätsverantwortlicher) Prof. Dr. Adrian Merlo (Dissertationsleiter) Dr. Brian A. Hemmings, FRS (Korreferent) Basel, den 21.06.2011 Prof. Dr. Martin Spiess Dekan “It’s not enough to say we are doing our best. We must succeed in doing what is necessary.” Winston Spencer Churchill Acknowledgement My first and outmost thanks go to my family for raising me to become a curious, independent and critical person interested in the beauty of nature and natural sciences. All I am today roots in my family. I am deeply grateful to Prof. Adrian Merlo for his trust in me and my work, his well measured guidance and help, his willingness to share his views and thoughts on science but also philosophy, and for his critical and thorough supervision of my thesis. Many people were involved in this piece of work in some way or the other and I would like to take the time to say thank you to all the members of the lab who were an invaluable help and also good friends; to Dr. Brian A. Hemmings for his generosity of giving me a place to work in difficult times as well as for his scientific support; to all the members of the CCRP glioma group for help, reagents and valuable comments and discussions; to all the members of my thesis committee for their help and valuable time; to Prof. Markus Rüegg for presenting this thesis to the faculty of science; to Oncosuisse, the SNF and the regional cancer league of Basel for financial support; to all my friends, fellow officers and colleagues who helped, supported, and shaped me to become who I am. Anita, thank you for your love, your support, your patience and your help… Inauguraldissertation Roland M. Huber Table of Contents Summary 2 Introduction 3 A Brief History of Cancer Cell Biology....................................................................... 5 The Case of Glioblastoma Multiforme ..................................................................... 9 Animal Models of HGG ............................................................................................ 19 The Cell of Origin – A Stem Cell gone Awry? ........................................................... 23 Results 29 Part 1 : The alternative Notch pathway via Deltex-1 is an oncogenic factor in malignant glioma…………………………………………………………………………………….. 29 Part 2 : In vivo modelling of gliomas and evaluation of therapeutic potential of low molecualr compounds…........................................................................ 70 Part 3 : GSK3β regulates differentiation and growth arrest in glioblastoma. ........... 95 Part 4 : Notch2 Signaling in Neural Stem Cells Promotes Features of Glioma Stem Cells..…………………………………………….……………………………………………….. 126 Future Perspectives 151 Six Hypotheses on the Future Perspectives of GBM Research and Therapy………… 151 Main Conclusions and Open Questions………………………………………………………………. 156 Our Results in Perspective…………………………………………………………………………………… 157 References (without results section) 162 Appendices 168 App I: “ETS Transcription Factor Erm Controls Subsynaptic Gene Expression in Skeletal Muscles”, Neuron, 2007...………………………………………………………….. 168 Curriculum Vitae 184 - 1 - Inauguraldissertation Roland M. Huber Summary Glioblastoma Multiforme is a WHO grade IV brain tumor with glial characteristics leading to more years of life lost than any other cancer. A better understanding of GBM biology and valid animal models are the two key elements to improved therapeutic results. We found Deltex1, which is part of an alternative Notch pathway, to activate both the PI3K/PKB and the MAPK/ERK pathway and to induce anti-apoptotic Mcl-1. DTX1 over- expression resulted in increased clonogenic and growth potential and also induced cell migration and invasion. Microarray gene expression analysis identified a DTX1-specific transcriptional program related to the changes in phenotype observed. Patients with low DTX1 levels have a favorable prognosis. Therefore, we propose the alternative Notch pathway via DTX1 as an oncogenic factor in glioblastoma. This could partially explain previous findings linking Notch status to prognosis wherein high Notch2 levels correlated with reduced patient survival. We found activated Notch2 in neural stem cells to induce glioma-inducing-cell features including increased proliferation, reduced apoptosis and astrocytic lineage commitment. These observations were found both in vitro and in vivo using a conditional mouse model. Together, these findings indicate an important role for Notch signaling (both canonical and non-canocical) in high grade glioma, offering a potential treatment target. We have also established an in vivo model of GBM which allowed us to analyze the efficacy of novel treatment regimens. Short term treatment of orthotopic xenograft gliomas in nude mice with histone deacetylase inhibitors and 2- deoxy-D-glucose resulted in prolonged survival, reduced tumor growth and induction of cancer cell apoptosis. Therefore, epigenetic reprogramming in combination with energy deprivation was found to have anti-tumor activity in vivo . In an independent project we identified GSK3β as a downstream target of Bmi1. GSK3β maintains a more stem cell like characteristic in GBM cells, potentially also in the glioma inducing cells. Several inhibitors to GSK3β exist and LiCl, which is often used in the clinic, correlates with reduced glioma incidence. Altogether, we believe we have added considerable knowledge on the biology of gliomas thereby helping to characterize the underlying events of gliomagenesis. Furthermore, we have established proof of principle for a novel treatment strategy in vivo . - 2 - Inauguraldissertation Roland M. Huber Introduction The human body consists of roughly 50 trillion (50*10 12 ) cells. Each one contains the full genetic information, but only uses a small fraction thereof to exert its biological function. The number of biological processes taking place in these cells is indicative of the likelihood of mistakes. While many, if not most processes are quenched by control mechanisms or redundant systems, some of them manifest and may cause malignant aberrations. A biological organism will be exposed to harmful effects ab initio . Internal effects like DNA replication errors, chromosomal dislocations or miss-segregations can occur throughout development or later in life. On top of that, an organism is exposed to a wide array of chemical, physical and biological influences potentially harmful to the genetic information. These errors accumulate over time in a growth selective process [1] eventually leaving the cell with a significantly altered genome which can ultimately cause uncontrolled growth and neoplastic disorders. Cancer is projected to become – and in the European Union it already is – the leading cause of death worldwide (Figure 1). The average age of the world population and the overall life expectancy is steadily increasing, giving mutations ever more time to accumulate in individual cells. Therefore, this trend appears to become even more sustained over the coming decades. Basically every human tissue can develop neoplastic disorders and usually there are several forms of tumors per tissue type, leaving a plethora of different diseases which all carry the inherent genetic variability of the individual. Currently we are still unable to determine individualized cancer profiles for patients due to technical and financial limits. However, with the rise of fast throughput and large scale analysis tools like microarrays or on-chip proteomics, there is hope to get closer to this approach. Fortunately there seem to be few, generally applicable concepts inherent to specific cancer subclasses offering a unifying understanding of the particular disease and indicating possible routes of treatment. - 3 - Inauguraldissertation Roland M. Huber Figure 1. Causes of death in the EU in 2006 (adapted from EUROSTAT survey 2006). In the EU-27 malignant neoplastic disorders were the leading cause of death in 2006. Y-axis shows related deaths per 100’000 inhabitants. Independent of the tumor type or location, several characteristic traits are found in all neoplastic disorders and are key features of cancer. Although the resulting feature may be the same, the underlying cause can be different. Several genotypes can lead to the same clinical phenotype. An overview of such traits and their underlying causes in general and in high grade gliomas (HGG) in particular are stated below. - 4 - Inauguraldissertation Roland M. Huber A Brief History of Cancer Cell Biology Seven features distinguish tumors and cancer cells from normal tissue [2]. They can be grouped into features which enable the cell to proliferate and grow even when not intended to, the ability to circumvent internal and external control mechanisms (e.g. immune evasion and neutralization of intrinsic apoptotic clearance), to ensure sufficient supply of nutrients and ultimately to disseminate. These traits can be related to malignant changes in seven distinct cellular mechanisms: Cell Growth. A normal cell cannot grow in the absence of specific, growth promoting signals. These signals are usually external – either soluble factors or
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