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Micrornas Drive Pancreatic Tumorigenesis and Progression: a Dissertation

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Micrornas Drive Pancreatic Tumorigenesis and Progression: a Dissertation University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2015-04-13 Subtle Controllers: MicroRNAs Drive Pancreatic Tumorigenesis and Progression: A Dissertation Brian J. Quattrochi University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Cancer Biology Commons, Genetics and Genomics Commons, Neoplasms Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons, and the Oncology Commons Repository Citation Quattrochi BJ. (2015). Subtle Controllers: MicroRNAs Drive Pancreatic Tumorigenesis and Progression: A Dissertation. GSBS Dissertations and Theses. https://doi.org/10.13028/M28P41. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/776 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. SUBTLE CONTROLLERS: MICRORNAS DRIVE PANCREATIC TUMORIGENESIS AND PROGRESSION A Dissertation Presented By Brian Joseph Quattrochi Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY April 13, 2015 Medical Scientist Training Program (MSTP) SUBTLE CONTROLLERS: MICRORNAS DRIVE PANCREATIC TUMORIGENESIS AND PROGRESSION A Dissertation Presented By Brian Joseph Quattrochi The signatures of the Dissertation Defense Committee signify completion and approval as to style and content of the Dissertation. _____________________________________________________ Brian Lewis, Ph.D., Thesis Advisor _____________________________________________________ Narendra Wajapeyee, Ph.D., Member of Committee _____________________________________________________ Victor Ambros, Ph.D., Member of Committee _____________________________________________________ Michelle Kelliher, Ph.D., Member of Committee _____________________________________________________ Michael Lee, Ph.D., Member of Committee The signature of the Chair of the Committee signifies that the written dissertation meets the requirements of the Dissertation Committee. _____________________________________________________ Art Mercurio, Ph.D., Chair of Committee The signature of the Dean of the Graduate School of Biomedical Sciences signifies that the student has met all graduation requirements of the school. _____________________________________________________ Anthony Carruthers, Ph.D., Dean of the Graduate School of Biomedical Sciences Medical Scientist Training Program (MSTP) April 13, 2015 iii © Copyright by Brian Joseph Quattrochi 2015 iv To Jenn: Without you, this thesis would not have been possible. You are here, in these pages, a silent partner in every experiment, the supporting shoulder of every late night. I can think of no other self-aware assemblage of stardust with whom I’d rather spend my life exploring the cosmos. v ACKNOWLEDGMENTS I must first thank my mentor, Brian Lewis, for his generosity in taking me on as a graduate student all those years ago. His patience over my many years of training and growth are deeply appreciated. I must also thank the members of the Lewis lab for their support and assistance, especially Jiu-Feng Cai for her technical assistance in the mouse room, and Makoto Sano for his careful teaching of histological techniques and expert pathological analyses. David Driscoll and Leanne Ahronian deserve immense credit as steadfast coworkers who have been supportive, helpful, and tolerant of my companionship these past six years. Lihua (Julie) Zhu provided bioinformatics support for the Dicer project, for which I am grateful. I must also thank Mike Lee for collaborating with us and providing critical statistical and intellectual input on that project. David Klimstra provided diagnostic pathological expertise to my tumor studies, and Chris Turner and Anushree Gulvady generously gave their time and expertise in the execution of invadopodia experiments. I am deeply grateful for their contributions to this work. Melissa Little provided absolutely essential support in the preclinical drug trial and demonstrated outstanding technical expertise and commitment to the care of my animals. I am also very thankful to Steve Jones for generously sharing the Dicerflox mice with us. Victor Ambros, Michelle Kelliher, Nathan Lawson, Mike Lee, and Art Mercurio deserve special recognition for serving as members of my thesis research advisory committee. You have consistently challenged me to improve as a scientist and your time and attention to my research are truly appreciated. I am vi also grateful for Narendra Wajapeyee’s willingness to come from Yale to serve as my external examiner for the defense. I have benefitted from the expertise and perspective of my many friends and colleagues in the Molecular Cell and Cancer Biology Department and the MSTP program. Your contributions over the years have helped to shape me as a scientist and our journey together has been a memorable one. Nina Bhabhalia, Liz Nourse, Pat Keith, and Shanna Spencer have tirelessly supported the department and our lab for years, and I am forever indebted to them for their help. To my family, who has provided me with unwavering support and encouragement throughout my entire life and especially during these past years in pursuit of my Ph.D., you have my undying love and gratitude. My brilliant and devoted partner, Jennifer Ziegenfuss, Ph.D., has been a pillar of support and an anchor during this monumental effort, and it is to her that I dedicate this work. vii ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies in the United States, with an average five-year survival rate of just 6.7%. One unifying aspect of PDAC is mutational activation of the KRAS oncogene, which occurs in over 90% of PDAC. Therefore, inhibiting KRAS function is likely an effective therapeutic strategy for this disease, and current research in our lab and others is focused on identifying downstream effectors of KRAS signaling that may be therapeutic targets. miRNAs are powerful regulators of gene expression that can behave as oncogenes or tumor suppressors. Dysregulation of miRNA expression is commonly observed in human tumors, including PDAC. The mir-17~92 cluster of miRNAs is an established oncogene in a variety of tumor contexts, and members of the mir-17~92 cluster are upregulated in PDAC, but their role has not been explored in vivo. This dissertation encompasses two studies exploring the role of miRNAs in pancreatic tumorigenesis. In Chapter II, I demonstrate that deletion of the mir- 17~92 cluster impairs PDAC precursor lesion formation and maintenance, and correlates with reduced ERK signaling in these lesions. mir-17~92 deficient tumors and cell lines are also less invasive, which I attribute to the loss of the miR-19 family of miRNAs. In Chapter III, I find that Dicer heterozygosity inhibits PDAC metastasis, and that this phenotype is attributable to an increased sensitivity to anoikis. Ongoing experiments will determine whether shifts in particular miRNA signatures between cell lines can be attributed to this viii phenotype. Together these findings illustrate the importance of miRNA biogenesis, and the mir-17~92 cluster in particular, in supporting PDAC development and progression. ix TABLE OF CONTENTS TITLE PAGE ........................................................................................................... i SIGNATURE PAGE .............................................................................................. ii DEDICATION ....................................................................................................... iv ACKNOWLEDGMENTS ...................................................................................... v ABSTRACT .......................................................................................................... vii TABLE OF CONTENTS ....................................................................................... ix LIST OF TABLES .................................................................................................. 1 LIST OF FIGURES ................................................................................................ 2 LIST OF THIRD-PARTY COPYRIGHTED MATERIAL ................................... 4 LIST OF ABBREVIATIONS ................................................................................. 5 PREFACE ............................................................................................................... 6 CHAPTER I Introduction ............................................................................................................. 7 Normal Pancreas ............................................................................................... 10 Neoplasia........................................................................................................... 14 Demographics ............................................................................................... 14 Initiation and Progression ............................................................................. 16 Detection, Staging, and Treatment................................................................ 19 Molecular Biology .......................................................................................
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