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The Role of the CXCR3 Signaling Axes in Pancreatic Ductal Adenocarcinoma

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The Role of the CXCR3 Signaling Axes in Pancreatic Ductal Adenocarcinoma University of Nebraska Medical Center DigitalCommons@UNMC Theses & Dissertations Graduate Studies Spring 5-9-2020 The Role of the CXCR3 Signaling Axes in Pancreatic Ductal Adenocarcinoma Andrew C. Cannon University of Nebraska Medical Center Follow this and additional works at: https://digitalcommons.unmc.edu/etd Part of the Bioinformatics Commons Recommended Citation Cannon, Andrew C., "The Role of the CXCR3 Signaling Axes in Pancreatic Ductal Adenocarcinoma" (2020). Theses & Dissertations. 449. https://digitalcommons.unmc.edu/etd/449 This Dissertation is brought to you for free and open access by the Graduate Studies at DigitalCommons@UNMC. It has been accepted for inclusion in Theses & Dissertations by an authorized administrator of DigitalCommons@UNMC. For more information, please contact [email protected]. The Role of the CXCR3 Signaling Axes in Pancreatic Ductal Adenocarcinoma By Andrew C. Cannon A DISSERTATION Presented to the Faculty of the University of Nebraska Graduate College in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Biochemistry and Molecular Biology Graduate Program Under the Supervision of Professor Surinder K. Batra University of Nebraska Medical Center Omaha, Nebraska February 2020 Supervisory Committee: Rakesh K. Singh, Ph.D. Joyce Solheim, Ph.D. Apar K. Ganti, M.D. Sushil Kumar, Ph.D. Sarah Thayer, M.D/Ph.D. ii To my Wife and Son, Taylor and Jack Cannon For your continuous love, support, patience, and perspective (even if given unknowingly) You are among my greatest joys, truest vulnerabilities and most profound motivations To my parents, John and Staci Cannon For the love you have shown me, the values you have instilled in me, and the opportunities you have afforded me To my friends, For sharing in my joy and sorrow throughout my training iii Acknowledgments The form of this thesis is two-fold. Superficially, it is the presentation of data derived the scientific works that I conducted over the past four years, the justification for that work in the form of previous scientific reports, the interpretation of the data in light of the broader scientific community, and what the findings may ultimately mean for the field. However, presented just beneath the tables, figures and references is a different story; a story that is not about signaling cascades or the metastatic process, but rather the development of an individual into a more formed scientist. While this story cannot be read directly from the text contained in this volume, the climax can be surmised by those who have written their own duplicitous works and, by this, understand the development that has occurred. It is my understanding that this second story is the reason that a thesis is required for graduation from a Ph.D. program and the cause of the celebration that accompanies the occasion. Because of the two-fold nature of this thesis, these acknowledgments must also be two-fold to fully acknowledge the contributions that were made to these two stories. At the outset of these acknowledgments, I must state that I claim neither of the stories presented here as wholly my own; they are the product of the unmeasurable efforts of the people involved in my graduate education. Nonetheless, I am proud of and humbled by the scientific work and personal development that has occurred as a result of my training. I pray with the deepest sincerity that all the people involved in my training will derive pride and satisfaction from the work presented here and the continuation of my scientific career. This work would not have been possible without the support, guidance, expertise, and mentorship of my mentor Dr. Surinder K. Batra. His support provided both the iv resources and confidence to develop a project, pursue my ideas, and hone my technical skills. Dr. Batra's wealth of knowledge, which he generously shared, focused my ambitions and efforts, challenged my conceptualization of science, and propelled me through the times during which I didn't know how to progress. In this capacity, Dr. Batra was patient without allowing stagnation, and through this, I learned even in failure. Technically, Dr. Batra's influence grounded my thinking in the fundamentals of biochemistry, which were ultimately a tremendous contribution to the completion of the work described here. Finally, Dr. Batra's criticism of my work was, at times, sharp, but correctly so. This criticism guided me to a higher standard for my work, thereby improving both the data I collected and my approach to science. His experience was a foundation that allowed me to navigate through the world of science at this early time in my career. It was through Dr. Batra's experience that I learned to manage the enthusiasm and excitement accompanying new ideas. Without this discipline, it is unlikely that I would have formed as cohesive of a story as is presented in this dissertation. Finally, Dr. Batra's mentorship showed me the type of scientist that I aim to be. For all of your contributions, I wish to express my deepest gratitude. This work owes much to Dr. Sushil Kumar, without whom I would have struggled more than was strictly necessary. Dr. Kumar’s guidance was critical to the growth of my technical skills during the completion of this project and was instrumental in the acquisition of the data presented herein. Furthermore, Dr. Kumar's constant pursuit of innovative and conceptual research was both the foundation for this work and a relentless impetus for me to expand my understanding of biochemistry and cancer biology. Dr. Kumar's patience was also critical to the completion of this work and my development as a scientist. This patience v allowed us to strive to find the “real biology” underlying CXCR3 in pancreatic cancer. As a result, I gained exposure to many fields in cancer biology, generated more hypotheses than I care to count, and ultimately became comfortable working in unfamiliar academic areas. Dr. Kumar’s patience facilitated my growth as a scientist in two main ways. First, this patience allowed me to try and fail and ultimately learn how to better conceptualize and plan experiments from beginning to end. Through these failures, I learned when to give up on a line of investigation and when to persist, and finally, I grasped what it means to carry out science. Furthermore, Dr. Kumar's patience facilitated the sometimes-heated scientific discussions that were so instrumental to my understanding of the project, my conceptualization of the field, and my development as a more rounded scientist. I have enjoyed these discussions, especially the heated ones, immensely over the years, and hope that you have as well. Finally, I acknowledge that Dr. Kumar’s friendship has been a tremendous help in the completion of my Ph.D. training. While not a typical friendship, it contained the necessary components; you shared in my joy and excitement as well as my frustrations. The impact of this on the completion of this work should not be underestimated. For all of these contributions, I am indebted to you. I must also acknowledge all the members of my supervisory committee: Dr. Rakesh Singh Ph.D., Dr. Joyce Solheim Ph.D., Dr. Apar Ganti M.D., and Dr. Sarah Thayer M.D./Ph.D. Each of these members has helped guide me in their own way during my Ph.D. This guidance helped me navigate difficult career situations and surmount technical challenges. Furthermore, the members of my supervisory committee served as a wealth of knowledge, which informed my work on this project to a significant extent, ultimately vi improving the quality of the research. Finally, these committee members were a critical source of encouragement during the challenges that I encountered over the past four years. I appreciate all that each of you has done to help me during my training; without you, my work would not be as meaningful as it is. To Drs. Justin Mott, Shelley Smith, and Debra Romberger, the directors of the UNMC M.D./Ph.D. program (during my stay here), I thank you for welcoming me into your program. Without this opportunity, it is unlikely that I would have been able to pursue both medicine and research, which has, to this point, culminated in the completion of this work, among others. I must also thank you for advocating on my behalf and serving as a source of reassurance during my time at UNMC. You each have comforted me in times that were unsettling. Through this, you provided me with the resources and confidence to move forward. I will always regard your mentorship and insight as being of the highest quality and value. I thank all the members of the Batra lab. Many of you have been valuable sources of technical knowledge, scientific insight, and at times comic relief. You have genuinely eased this training process and made it more enjoyable. I would especially like to thank Kavita Mallaya for her support over the years. She put in hours of time and effort to ensure that I had the reagents and specimens I needed to carry out my work so that I could focus on the experiment and data. Additionally, I want to thank Christopher Thompson. Throughout my Ph.D., Chris has been a friend of the highest caliber. He has been a constant source of encouragement, an essential resource for learning new skills, a sounding board for novel ideas, a valued critic, and a vent for frustrations. He shared in almost all aspects of my training and allowed me to do the same with his training. I consider myself lucky to vii have had the opportunity to work with Chris. I also owe gratitude to Dr. Rakesh Bhatia.
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