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Egfr Activates a Taz-Driven Oncogenic Program in Glioblastoma

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Egfr Activates a Taz-Driven Oncogenic Program in Glioblastoma EGFR ACTIVATES A TAZ-DRIVEN ONCOGENIC PROGRAM IN GLIOBLASTOMA by Minling Gao A thesis submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland March 2020 ©2020 Minling Gao All rights reserved Abstract Hyperactivated EGFR signaling is associated with about 45% of Glioblastoma (GBM), the most aggressive and lethal primary brain tumor in humans. However, the oncogenic transcriptional events driven by EGFR are still incompletely understood. We studied the role of the transcription factor TAZ to better understand master transcriptional regulators in mediating the EGFR signaling pathway in GBM. The transcriptional coactivator with PDZ- binding motif (TAZ) and its paralog gene, the Yes-associated protein (YAP) are two transcriptional co-activators that play important roles in multiple cancer types and are regulated in a context-dependent manner by various upstream signaling pathways, e.g. the Hippo, WNT and GPCR signaling. In GBM cells, TAZ functions as an oncogene that drives mesenchymal transition and radioresistance. This thesis intends to broaden our understanding of EGFR signaling and TAZ regulation in GBM. In patient-derived GBM cell models, EGF induced TAZ and its known gene targets through EGFR and downstream tyrosine kinases (ERK1/2 and STAT3). In GBM cells with EGFRvIII, an EGF-independent and constitutively active mutation, TAZ showed EGF- independent hyperactivation when compared to EGFRvIII-negative cells. These results revealed a novel EGFR-TAZ signaling axis in GBM cells. The second contribution of this thesis is that we performed next-generation sequencing to establish the first genome-wide map of EGF-induced TAZ target genes. To further define EGF-induced TAZ target genes, we performed RNA-sequencing and TAZ ChIP-sequencing in EGF-treated GBM neurospheres. Using KEGG pathway analysis followed by extensive validation, we found that TAZ acts downstream of EGFR to activate multiple oncogenic signaling pathways, including key components of the RTK signaling pathway to form an EGFR-TAZ-RTK positive feedback loop, and other oncogenic genes, which form a EGFR- ii TAZ-driven network to promote GBM growth, invasion, stemness, therapeutic resistance and immune escape. To further study the oncogenic effects of the EGF-induced TAZ hyperactivation in GBM cells, we found that enforced TAZ expression promoted GBM cell proliferation, invasion, radioresistance and tumorigenicity. Our results and discoveries from others all suggested that TAZ is a potential drug target for GBM therapy. Based on the EGFR-TAZ signaling axis model, we tested a set of brain- penetrating RTK inhibitors and the TAZ inhibitor Verteporfin (VP) for their abilities to inhibit TAZ signal in GBM cells. Besides VP, Osimertinib, a third-generation EGFR inhibitor most potently inhibited TAZ and its gene targets both in vitro and in vivo. It also effectively inhibited GBM xenograft growth and extended the survival of tumor-bearing mice. In summary, our discoveries reveal a novel EGFR-TAZ signaling axis that promotes GBM malignancy, and provides preclinical evidence to justify future clinical applications of VP, OS, and other similar brain-penetrating EGFR inhibitors for targeting TAZ-associated GBM and possibly other primary or metastatic brain tumors. Together, this thesis elucidates a novel EGFR-TAZ signaling axis in GBM and further provides a genome-wide map of downstream transcriptome that promotes key malignant features of GBM. Our results also support the clinical use of defined FDA-approved EGFR inhibitor OS and the FDA-approved drug VP for effective TAZ targeting in GBM and possibly other primary or metastatic brain tumors with TAZ hyperactivation. Primary Reader and Advisor: John Laterra Secondary Reader: Charles Eberhart iii Acknowledgments Graduate school is one of the most precious periods in my life, full of challenges and excitement. It would be impossible for me to make it to the end without all the support and help I received along this process. First, I would like to thank Dr. John Laterra for his mentorship. Your work attitude and ethic is inspiring and encouraging. And I also want to thank Dr. Mingyao Ying for the direct guidance through this project. Second, I would like to thank my thesis committee members: Dr. Charles Eberhart, Dr. Edward Gabrielson, Dr. Mingyao Ying, and Dr. John Laterra for their thought provoking discussions and professional guidance throughout my thesis. I am also most grateful for all the scientific and personal help for Dr. Laterra’s group: Bachchu, Hernando, Qingfu, Yingchao, Shuang, Chengchen, Emma, Tengjiao, Qian, Fenghong, Yi, Dr. Li, and Dr. Xia. Special thanks to Dr. Yi Fu for all his help in animal experiments. I would also like to thank Dr. Rodriguez, Dr. Eberhart, and Dr. Nix for introducing me to the world of neuropathology and eye pathology. I want to thank Mrs. Margaret Lee and Mr. Al Lee for their kind support and scholarship. Also, the supportive atmosphere of the Pathobiology department and numerous help from Stacey and Tracy are critical for this process. And I am thankful for all the support I received from KKI 4th floor. Last but not least, I would like to thank my parents and friends for their unconditional love and support throughout my life. iv Contents Abstract .................................................................................................................................... ii Acknowledgments .................................................................................................................. iv Content ..................................................................................................................................... v List of Tables ......................................................................................................................... vii List of Figures ......................................................................................................................... ix Abbreviations ......................................................................................................................... xi Chapter 1: Introduction ......................................................................................................... 1 1.1 Glioblastoma .................................................................................................................... 1 1.2 Receptor Tyrosine Kinase and Epidermal Growth Factor Receptor ............................... 7 1.3 The Hippo Signaling Pathway and TAZ/YAP .............................................................. 12 1.4 Rationale and Hypothesis .............................................................................................. 17 Chapter 2: EGF induces TAZ transcription through EGFR and its downstream kinase pathway .................................................................................................................................. 20 2.1 Introduction ................................................................................................................... 20 2.2 Materials and Methods .................................................................................................. 21 2.3 Results ........................................................................................................................... 23 2.4 Conclusion and Discussion ........................................................................................... 27 Chapter 3: TAZ acts as a key mediator of EGF signaling to activate oncogenic cascades in GBM ................................................................................................................................... 43 3.1 Introduction ................................................................................................................... 43 3.2 Materials and Methods .................................................................................................. 44 v 3.3 Results ........................................................................................................................... 47 3.4 Conclusion and Discussion ........................................................................................... 50 Chapter 4: TAZ hyperactivation promotes GBM growth, invasion, and tumorigenicity .................................................................................................................................................. 63 4.1 Introduction ................................................................................................................... 63 4.2 Materials and Methods .................................................................................................. 63 4.3 Results ........................................................................................................................... 65 4.4 Conclusion and Discussion ........................................................................................... 67 Chapter 5: The EGFR inhibitor Osimertinib and TAZ inhibitor Verteporfin potently inhibits the TAZ-driven oncogenic program in GBM cells and xenografts .................... 79 5.1 Introduction ................................................................................................................... 79 5.2 Materials and Methods .................................................................................................. 80 5.3 Results ..........................................................................................................................
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