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Downloaded 18 July 2014 with a 1% False Discovery Rate (FDR) UC Berkeley UC Berkeley Electronic Theses and Dissertations Title Chemical glycoproteomics for identification and discovery of glycoprotein alterations in human cancer Permalink https://escholarship.org/uc/item/0t47b9ws Author Spiciarich, David Publication Date 2017 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California Chemical glycoproteomics for identification and discovery of glycoprotein alterations in human cancer by David Spiciarich A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Chemistry in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Carolyn R. Bertozzi, Co-Chair Professor David E. Wemmer, Co-Chair Professor Matthew B. Francis Professor Amy E. Herr Fall 2017 Chemical glycoproteomics for identification and discovery of glycoprotein alterations in human cancer © 2017 by David Spiciarich Abstract Chemical glycoproteomics for identification and discovery of glycoprotein alterations in human cancer by David Spiciarich Doctor of Philosophy in Chemistry University of California, Berkeley Professor Carolyn R. Bertozzi, Co-Chair Professor David E. Wemmer, Co-Chair Changes in glycosylation have long been appreciated to be part of the cancer phenotype; sialylated glycans are found at elevated levels on many types of cancer and have been implicated in disease progression. However, the specific glycoproteins that contribute to cell surface sialylation are not well characterized, specifically in bona fide human cancer. Metabolic and bioorthogonal labeling methods have previously enabled enrichment and identification of sialoglycoproteins from cultured cells and model organisms. The goal of this work was to develop technologies that can be used for detecting changes in glycoproteins in clinical models of human cancer. In Chapter 1 of this dissertation, I present an overview of the structures and functions of glycans and their relationship to cancer progression. I also discuss applications of in vivo bioorthogonal labeling in model organisms and how in humans, the significant regulatory and ethical barriers associated with introducing chemically altered sugars into people have hindered it. Finally, I review mass spectrometry-based proteomics and how it can be applied to clinical glycoproteomics. In Chapter 2, I demonstrate the first application of this bioorthogonal labeling in a glycoproteomics platform applied to human tissues cultured ex vivo. Both normal and cancerous prostate tissues were sliced and cultured in the presence of functionalized derivatives of N-acetyl mannosamine, the sialic acid biosynthetic precursor. Chemical biotinylation followed by enrichment and mass spectrometry led to the identification of glycoproteins that were found at elevated levels or uniquely in cancerous prostate tissue. This work therefore extends the use of bioorthogonal labeling strategies to problems of human clinical relevance. Secretome proteins play important roles in regulation of many physiological processes and show utility as potential biomarkers and for noninvasive diagnostics and treatment monitoring. In Chapter 3, I discuss a platform for identifying sialoglycoproteins that were secreted in the conditioned media from bioorthogonally labeled human prostate tissue - 1 - Abstract slice cultures. This platform could be used to identify disease biomarkers in a faithful clinical model of human disease. Mutations in granulocyte colony-stimulating factor 3 receptor (CSF3R), also known as G- CSFR, occur in the majority of patients with chronic neutrophilic leukemia (CNL) and are more rarely present in other kinds of leukemia. In Chapter 4, I discuss novel variants in CSF3R at asparagine residue N610, one of which was germline. Interestingly, these N610 substitutions are potently oncogenic and result in ligand-independent receptor activation. They confer activation of the JAK-STAT signaling pathway and concurrent sensitivity to JAK kinase inhibitors. The N610 residue is part of a consensus N-linked glycosylation motif in the receptor. Detailed mass spectrometry analysis demonstrates that this site is occupied by both complex and complex bisecting glycans. Further analysis demonstrates that N610 is the primary site of sialylation of the receptor. This study demonstrates that membrane-proximal N-linked glycosylation is critical for maintaining the ligand dependence of the receptor. Furthermore, it expands the repertoire of potently oncogenic mutations in CSF3R that are therapeutically targetable - 2 - This dissertation is dedicated to my family and friends for all their support. With great appreciation to my mom, sister, and Giorgio. - i - Chemical glycoproteomics for identification and discovery of glycoprotein alterations in human cancer Table of Contents List of Figures ................................................................................................................... iv List of Tables .................................................................................................................... vi List of Abbreviations ........................................................................................................ vii Acknowledgments ............................................................................................................ ix Chapter 1. Glycoproteomics and unnatural sugars to study protein glycosylation .................................................................................................................... 1 1.1 Introduction .......................................................................................................... 1 1.2 Glycosylation is part of the cancer phenotype .................................................... 4 1.3 Mass spectrometry-based glycoproteomics ....................................................... 6 1.4 Unnatural sugars for bioorthogonal enrichment of glycans ................................ 9 1.5 Conclusion ........................................................................................................ 12 1.6 References ....................................................................................................... 13 Chapter 2. Bioorthogonal labeling of human prostate cancer tissue slice cultures for glycoproteomics ...................................................................................................... 22 2.1 Introduction ........................................................................................................ 22 2.2 Results .............................................................................................................. 24 2.3 Discussion ........................................................................................................ 34 2.4 Methods and Materials ..................................................................................... 37 2.5 Code ................................................................................................................. 40 2.6 References ....................................................................................................... 43 - ii - Table of Contents Chapter 3. Enrichment of sialoglycoproteins from human prostate tissue slice culture conditioned media ............................................................................................ 49 3.1 Introduction ........................................................................................................ 49 3.2 Results .............................................................................................................. 52 3.3 Conclusion ........................................................................................................ 60 3.4 Tables ............................................................................................................... 61 3.5 Methods and Materials ..................................................................................... 63 3.6 References ....................................................................................................... 68 Chapter 4. A novel germline variant in CSF3R reveals a N-glycosylation site that is important in receptor regulation ................................................................................. 73 4.1 Introduction ........................................................................................................ 73 4.2 Results .............................................................................................................. 74 4.3 Conclusion ........................................................................................................ 81 4.4 Tables ............................................................................................................... 85 4.5 Methods and Materials ..................................................................................... 88 4.6 References ....................................................................................................... 93 Appendices ................................................................................................................... 96 Appendix Table 1. Proteomic dataset of proteins found in normal prostate tissue slice cultures (TSCs) ....................................................................................................... 97 Appendix Table 1. Proteomic dataset of proteins found in cancer prostate tissue slice cultures (TSCs) ....................................................................................................
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