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The Role of Tunneling Nanotubes in Mediating Intercellular Communication in Cancer

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The Role of Tunneling Nanotubes in Mediating Intercellular Communication in Cancer THE ROLE OF TUNNELING NANOTUBES IN MEDIATING INTERCELLULAR COMMUNICATION IN CANCER A DISSERTATION SUBMITTED TO THE FACULTY OF UNIVERSITY OF MINNESOTA BY Snider Desir IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNDER THE MENTORSHIP OF Emil Lou, MD, PhD February 2018 © Snider Desir, 2018 Acknowledgements I would like to thank my mentor, Dr. Emil Lou for providing me with the space and guidance to successfully carry out the dissertation research. There were areas, both scientific and non-scientific, in which I lack understanding. You made it a priority to meet with me weekly so we can work on those weaknesses. Your dedication to my progress made you a great mentor. Thank you. I would also like to offer thanks Dr. Cliff Steer who introduced me to the field of tunneling nanotubes, the Lou Lab, and allowed me to have open access to his own lab space. I want to thank Phillip Wong, our lab manager who has helped me tremendously throughout my time as a graduate student. Phil was my best pal in the lab and is someone who was often there to help me cope with the many difficulties of being a student. Furthermore, thank you to each and every individual who has ever been associated with the Lou Lab and played a role via bench work or through the writing of manuscripts. Special thanks to the past and current students of the IBP graduate program. During my time in the program, we have been a cohesive group of students who has done a lot to help one another. I want to thank the faculty for being so open to providing assistance to every student. Specifically, thank you to Dr. John Osborn who made sure I was always on path to successfully complete the program. Additionally, I want to thank the department staff including Jane Barnard, Randi Lundell, and Jean Otto for their contribution to the success of all the students. Thank you to Dr. Jon Gottesman who introduced me to the program and met with me often to inquire about how I was doing in this cold weather climate. Special thanks to Dr. Noro Andriamanalina. As a mentor, Dr. Andriamanalina worked to help me navigate this environment as a graduate student. Thank you to my thesis committee for acting more as co-mentors and always making the time to evaluate my progress both individually and as group. Dr. Lou, Dr. Katz, Dr. Subramanian, and Dr. Osborn: I appreciate your work in helping me develop scientifically. I could not have gotten to this point without your dedication to my progress. Finally, I want to thank Mr. Jeff Jones for helping me obtain admission into Kutztown University. I thank God for sending you on my path to facilitate the beginnings of this great accomplishment. i Dedication I would like to dedicate this thesis to the people who have made so many sacrifices in order for me to reach this point in life. It took an outstanding amount of support from close friends and family to make this happen. First, I would like to dedicate this great accomplishment to my brother and sister. Our parents passed when I was 6 years old and you both had to stop pursuing your own dreams to take care of me. Ronald and Roseline, there is absolutely no way I can repay you for what you have done and what you have endured for me. I want to also dedicate this thesis to Roxanna Wright. You took me into your home and gave me a new family that has continued to support me until this very day. One the biggest turning point in my life was when you walked into my 9th class and signed me up for your performing arts class. Lastly, I would like to dedicate this thesis to my wife, Michelle. I could not have done this without you. It is by no coincidence that the two of us from completely different worlds ended up coming to Minnesota for graduate school. You have always believed in me and my dreams. Your support and encouragement are unparalleled. Thank you for loving me, being my best friend, and my better half. ii Table of contents Acknowledgements ............................................................................................................. i Dedication .......................................................................................................................... ii Table of contents .............................................................................................................. iii List of tables ...................................................................................................................... v List of figures .................................................................................................................... vi Chapter One - Introduction .............................................................................................. 1 1.1 Overview of the problem ......................................................................................... 2 1.2 The hallmarks of cancer .......................................................................................... 4 1.3 The tumor microenvironment ................................................................................ 12 1.4 Intercellular communication in cancer .................................................................. 16 Chapter Two – Intercellular communication in malignant pleural mesothelioma: properties of tunneling nanotubes ....................................................... 24 2.1 Synopsis ................................................................................................................. 25 2.2 Introduction ........................................................................................................... 26 2.3 Methods ................................................................................................................. 31 2.4 Results ................................................................................................................... 41 2.5 Discussion .............................................................................................................. 52 Chapter Three – Tunneling nanotube formation is stimulated by hypoxia in ovarian cancer cells ........................................................................................................ 66 3.1 Synopsis ................................................................................................................. 67 3.2 Introduction ........................................................................................................... 68 3.3 Methods ................................................................................................................. 70 3.4 Results ................................................................................................................... 77 3.5 Discussion .............................................................................................................. 85 iii Chapter Four - Tunneling nanotube formation is upregulated in pancreatic cancer and mediates a novel long-distance method of intercellular drug efflux ................................................................................................................................ 98 4.1 Synopsis ................................................................................................................. 99 4.2 Introduction ........................................................................................................... 100 4.3 Methods ................................................................................................................. 102 4.4 Results ................................................................................................................... 107 4.5 Discussion .............................................................................................................. 113 Chapter Five - Summary .............................................................................................. ..125 Bibliography ................................................................................................................... ..133 iv List of tables CHAPTER 2 Intercellular communication in malignant pleural mesothelioma: properties of tunneling nanotubes Table 1: P-values from comparisons of TNTs Length in mesothelioma cells by cell line and time…………………………………………………………………………………65 v List of figures CHAPTER 1 Introduction Figure 1: The hallmarks of cancer……………………………………………....11 Figure 2: Tumor-stroma and tumor-tumor interactions play an important role in the heterogeneous tumor microenvironment…………………………………….23 CHAPTER 2 Intercellular communication in malignant pleural mesothelioma: properties of tunneling nanotubes Figure 1: Malignant mesothelioma cells form more TNTs than benign mesothelial cells………….……………………………………………………....53 Figure 2: TNT length decreases with time and with proliferation of mesothelioma cells……………………………….……………………………………………...55 Figure 3: TNT tethering of mesothelioma cells in in vitro models of pleural effusions……………………………………………………………………….....56 Figure 4: Effect of Migrastatin on TNT formation in MSTO cells..…………...58 Figure 5: 3-dimensional modeling of TNTs in vitro…………………………....59 Figure 6: Comparison of 2-dimensional histopathology section vs. 3-dimensional confocal imaging of primary human malignant mesothelioma tumors ex vivo, with specific examination for TNTs……………………………………………..60 Figure 7: Hyaluronic acid is not associated with TNTs….……………………...61 Figure 8: Decreased tumor growth and survival of mice implanted with TNT- primed mesothelioma cells……….……………………………………………...62 Figure 9: Gene expression profiling
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