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Loss of Tip30 Accelerates Pancreatic Cancer Progression LOSS OF TIP30 ACCELERATES PANCREATIC CANCER PROGRESSION AND METASTASIS Imade E. Imasuen Williams Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Doctor of Philosophy in the Department of Biochemistry and Molecular Biology, Indiana University July 2019 Accepted by the Graduate Faculty of Indiana University, in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Doctoral Committee ______________________________________ Thomas Hurley, Ph.D., Chair ______________________________________ Maureen Harrington, Ph.D. October 22, 2018 ______________________________________ Brittney-Shea Herbert, Ph.D. ______________________________________ Harikrishna Nakshatri, BVSc., Ph.D. ii © 2019 Imade E. Imasuen Williams iii DEDICATION I dedicate this dissertation to my late grandparents, Tamara and Mikhail Antonyuk, and my husband, Dwight Williams, as without them none of this would have been possible. iv ACKNOWLEDGEMENTS I would like to express my sincerest gratitude to my doctoral committee: Dr. Maureen Harrington, Dr. Brittney-Shea Herbert, Dr. Hari Nakshatri, and Dr. Thomas Hurley. Thank you for your scientific advisement, support, and guidance. Without your service I would not have made it this far. I would like to especially thank Dr. Thomas Hurley and Dr. Hari Nakshatri for co-advising me through the completion of my doctoral training and dissertation. I am also especially grateful for and am humbled by the entire committee’s dedication and feedback over the years, especially in regards to this dissertation and my grant writing. Your support and encouragement gave me an extraordinary amount of strength and courage. In addition to my committee, I would like to thank Dr. Francis Enane, Brandy Boyer- Wood (Indiana Biomedical Gateway (IBMG) Program for PhD Studies), Debra Barker (Indiana University Purdue-University of Indianapolis (IUPUI) Graduate Office), and Dr. Kimberly S. Collins for their feedback and assistance in regards to the formatting of this dissertation. I would like to express my sincerest gratitude to Dr. Murray Korc, and present and past members of the Korc Laboratory, especially Dr. Francis Enane, Samantha Deitz McElyea, Dr. Jesse Gore, Dr. Sudha Savant, Dr. Kelly Craven, Alison Bates, and Abass Conteh for their support and guidance during my doctoral training. I would like to thank my funding source, the National Institutes of Health (NIH) and National Cancer Institute (NCI). This work and my PhD training was supported by a Diversity Supplement to RO1-CA075059, and more recently by a Ruth L. Kirschstein National Research Service Award (NRSA) Individual v Predoctoral Fellowship to Promote Diversity in Health-Related Research (Parent F31) awarded by the NCI/NIH under Award Number F31-CA236332. I would like especially thank the Center to Reduce Cancer Health Disparities, especially Dr. Nicole McNeil Ford, for their professional development and grant writing workshops, and their support. I would also like to thank the Lustgarten Foundation for the travel award that allowed me to attend the 2017 Cold Spring Harbor Workshop on Pancreatic Cancer, as well as all the facilitators of the workshop. The experience truly enriched my research training in the field of pancreatic cancer. The interpretation of the mouse studies in this dissertation would not have been possible without Dr. George E. Sandusky, whom I would like to especially acknowledge and thank for the pathological evaluation of the tissues sections associated with these studies, and for allowing me to shadow and learn under his guidance. I would like to thank Rachael Topolski for assistance with tissue sectioning and thank Khalid Mohammad’s Laboratory for assistance with tissue processing. I thank Samantha Deitz McElyea for creating the AsPC-1-miR-10b- OX-GFP and AsPC-1-miR-10b-GFP-C human pancreatic cancer cell lines. I would like to thank Dr. Francis Enane for his expertise and assistance with whole genome sequencing and The Cancer Genome Atlas (TCGA) analyses. I would also like to thank the following individuals and research cores for supporting my work: Mary Brown and IU School of Medicine Indiana Center for Biological Microscopy for confocal microscopy training and guidance; Susan Perkins and the Department of Biostatistics walk-in clinic for guidance with statistical analyses; the Medical and Molecular Genetics Departments and Erica vi Clickenbeard for assistance with imaging; the Indiana University Simon Cancer Center (IUSCC) Flow Cytometry Core for the sorting of green fluorescent protein (GFP)-labeled cell lines; and Robert Brankamp from The Jackson Laboratory for his consultation on mouse strain genetics and resources for mice obtained from The Jackson Laboratory. The IU Simon Cancer Center Summer Research Program (IUCCSRP) first exposed me to the field of cancer research; and I would like to thank the IUCCSRP and my mentor Dr. Marc Mendonca, Helen Chin-Sinex, Dr. Joseph Dynlacht, and Dr. Gwendolyn Johnson, the program director at the time. I would also like to thank Dr. Robert J. Coffey and Dr. Michelle Demory Beckler, Dr. Patrick Ma, Dr. Periasamy Selvaraj, and Dr. Erica Bozeman for their mentorship during my baccalaureate and post-baccalaureate training. I am grateful for the Southern Regional Education Board especially Dr. Ansley Abraham and the Yale Ciencia Academy for providing me with networking and professional development resources for a career in science and education as well as moral support. I am grateful for the supportive faculty and staff at IU School of Medicine, especially, Dr. Millie Georgiadis, Dr. John Turchi, Dr. Travis Jerde, Dr. Hari Nakshatri, Dr. Teresa Zimmers, and Dr. Andrea Bonetto for support of my scientific development and training and enthusiastic support of opportunities for students to present their research through entities such as departmental seminars and the Cancer Research Club. I would like to thank the leadership of the IBMG Program for PhD Studies, especially Tara Hobson, Dr. Joseph Bidwell, and Brandy Boyer- Wood, the Biochemistry and Molecular Biology Department at IU School of vii Medicine, especially Graduate Advisor Dr. Mark Goebl, Grants Specialist Sheila Reynolds, Computer Support Specialist Jack Arthur, Melissa Tarrh, and Darlene Lambert; the IUPUI Graduate Office, especially Dr. Tabitha Hardy and Dr. Janice Blum, Kim Burrows, Vicki Bonds, Dr. Jason Kwon, and my cohort for their advice, mentorship, and feedback during my PhD training. The commitment of the IUPUI faculty and staff to pedagogy has been inspiring beyond measure. The IBMG program provided me with abundant access to opportunities and resources that enabled me to grow intellectually and professionally. It has been an absolute honor learning from and conversing with such a large pool of brilliant scientists with the highest caliber of intellect and creative thinking. Thank you all for seeing my potential, believing in me, and supporting me. And thank you for collectively preparing me for a very exciting future of endless possibilities. I owe many thanks to my center and foundation, God, and my husband, Dwight Williams. This would not have been possible without the unwavering love and support of my family and friends that saw me through this incredible journey and completion of this dissertation, especially, Ayshai Jones, and Frank and Sissy Wade, who were present every step of the way. Thank you. To my beloved mother- in-law, Meme, who passed away of metastatic breast cancer on October 23, 2013, the semester I began the PhD program, I would like to say thank you for your countless support. Your presence in my life made an everlasting impact and helped carry me through. Lastly, I would be remised to not acknowledge all those affected by cancer, poverty, or oppression, the reason behind my motivation and passion. viii Imade E. Imasuen Williams LOSS OF TIP30 ACCELERATES PANCREATIC CANCER PROGRESSION AND METASTASIS Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related death in the United States, and is characterized by key driver mutations (e.g. KRAS, TP53, CDKN2A, and SMAD4), elevated expression of growth factors such as TGF-βs and the EGF receptor (EGFR), a markedly desmoplastic stroma, and a propensity to develop multi-organ metastases and chemoresistance. Consistent with its aggressive nature, the 5-year survival rate for PDAC is 8-9%, which demonstrates an urgent need to develop novel therapies. High expression levels of microRNA-10b (miR-10b) in PDAC tissues are associated with decreased patient survival and earlier appearance of metastatic disease following neoadjuvant chemoradiotherapy. miR-10b downregulates the expression of transcription coactivator Tat-Interacting Protein 30 (TIP30) by targeting its 3’UTR. TIP30 has multiple reported functions. TIP30 suppresses tumor formation and metastasis, forms a complex that regulates EGFR trafficking and degradation, and transcriptionally upregulates pro-apoptotic genes. Alterations in TIP30 have been reported in multiple human cancers, including pancreatic cancer. We hypothesized that Tip30-deficiency accelerates PDAC progression and metastasis in a murine model of PDAC. To test this hypothesis, we crossed mice with oncogenic Kras (KC) localized to the pancreas epithelium, with Tip30-deficient mice (K30C). We compared PDAC histopathology between Tip30-heterozygous (K30+/-C) and Tip30-null (K30-/-C) mice. Tip30-heterozygosity ix accelerated PDAC-lesion-associated
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