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Defining Sources of Nutrient Limitation for Tumors By Defining sources of nutrient limitation for tumors by Mark Robert Sullivan B.S. Molecular Biology and Chemistry University of Pittsburgh (2013) Submitted to the Department of Biology in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY June 2019 © 2019 Mark R. Sullivan. All rights reserved. The author hereby grants to MIT permission to reproduce and to distribute publicly paper and electronic copies of this thesis document in whole or in part in any medium now known or hereafter created. Signature of Author.......................................................................................................................... Department of Biology April 30, 2019 Certified by ...................................................................................................................................... Matthew G. Vander Heiden Associate Professor of Biology Thesis Supervisor Accepted by...................................................................................................................................... Amy E. Keating Professor of Biology Co-Director, Biology Graduate Committee 1 2 Defining sources of nutrient limitation for tumors by Mark Robert Sullivan Submitted to the Department of Biology on April 30, 2019 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Biology ABSTRACT Tumor growth requires that cancer cells accumulate sufficient biomass to grow and divide. To accomplish this, tumor cells must acquire various nutrients, and growth slows if these metabolites are not obtained in sufficient quantities. Importantly, the metabolic demands of cancer cells can be different from those of untransformed cells, and nutrient accessibility in tumors is different than in normal tissues. Thus, tumor survival and growth may be limited by different metabolic factors than those that are necessary to maintain non-cancerous cells. This dissertation examines sources of nutrient limitation in tumors. We study the role of the amino acid serine in tumor growth and show that endogenous serine availability restrains growth of breast tumors. We also demonstrate that breast cancer and melanoma can overcome physiological serine limitation by upregulating expression of the serine synthesis pathway enzyme phosphoglycerate dehydrogenase (PHGDH). To further study amino acid and nucleotide metabolism in tumor growth, we examine the role of the enzyme methionine synthase (MTR) in tumor progression. MTR is involved in both methionine synthesis and folate metabolism and may be important for tumor progression. We find that MTR is required to maintain intracellular levels of both S-adenosyl methionine and nucleotides, but not methionine. We observe that MTR is dispensable for growth in standard culture media, but essential in media containing the folate source available in blood. Further, MTR is essential for folate metabolism and tumor growth in vivo. The conditional requirement for MTR depending on the source of extracellular folate highlights the importance of understanding which nutrients are available to tumors in vivo, as nutrient accessibility can determine whether a given metabolite or pathway is limiting for tumor growth. To define the nutrient environment present in tumors, we quantitatively profile the metabolites present in tumor interstitial fluid (TIF). We find that the nutrients available to tumors in TIF differ from those present in circulation. Further, by comparing TIF nutrient levels between murine cancer models, we find that tumor type, anatomical location and animal diet affect local nutrient availability. Together, these studies provide new insight into sources of nutrient limitation in tumors. Thesis supervisor: Matthew G. Vander Heiden Title: Associate Professor of Biology 3 ACKNOWLEDGEMENTS This dissertation was only made possible by the constant advice and support that I received from many people over the last few years. I first want to thank my advisor Matthew Vander Heiden for his enthusiasm and unconditional support. Matt gave me great license to explore the areas of biology that I found most exciting and encouraged me to build my own approach to experimentation and scientific thought. His willingness to allow me that freedom but to also express incredible enthusiasm and always offer his help and support has provided me with an ideal environment to generate ideas and has been invaluable to my growth as a scientist. I feel fortunate to have joined Matt’s lab, and I will always be grateful to him for the positive and productive experience I have had there. I would like to thank my thesis committee, Jacqueline Lees and Jing-Ke Weng. Jackie and Jing-Ke have provided me with many useful discussions about both my project and my career and have always been willing to give me a different perspective to consider. I’d also like to thank Marcia Haigis for taking the time to serve as my outside committee member. I would like to acknowledge all of the members of the Vander Heiden lab past and present for helping to foster such a friendly and collaborative environment. I’ve been lucky to overlap with almost every person who has been a part of the Vander Heiden lab to this point, and it has been incredible to have such thoughtful, helpful people surrounding me as I’ve progressed through my PhD. I feel that I was able to learn something from nearly every person that I’ve shared time with in the lab, and I’ve constantly enjoyed all of their company. I particularly want to thank Katie Mattaini; Katie recruited me to the lab, served as my first mentor, and handed off an amazing project for me to work on. Most importantly, Katie is a lovely human being who has consistently served as a role model for me. I’d like to thank Aaron Hosios for teaching me about essentially every topic imaginable, from how to approach science to how to be an effective teacher. Aaron is an incredible font of knowledge and has always been willing to give his time to help me learn. Much of the work described in this dissertation was derived from ideas generated by Aaron, and I could not be more grateful for his constant support and friendship. I also owe a lot to Alex Muir. For the last few years of my PhD, Alex and I have discussed at length just about every idea that either of us has generated, scientifically or philosophically. Those discussions have been essential to my growth as a scientist and as a person. Alex’s thoughtfulness and wit have enriched my lab experience greatly, and I’m very thankful for his friendship. I want to thank Dan Gui for his scientific insight, but also for countless games of basketball together. I’d like to thank Laura Danai; nobody gives better advice, scientifically or personally, and nobody else makes lab as enjoyable as Laura. I’d like to thank Anna Nguyen for always brightening everyone’s day in lab and for her help maintaining mice, no matter how much dander they had. I also want to thank Emily Dennstedt; Emily’s enthusiasm is infectious and her technical skills were vital for much of the work described in this dissertation. I want to thank Allison Lau for being the best baymate I could have asked for, for her scientific and career advice, and for always stepping up her cake-making game on my birthday. I’d like to thank Zhaoqi Li for always having creative ideas and for many helpful 4 conversations. I want to thank Caroline Lewis for being an original part of team serine, but also for her constant help with mass spectrometry. I’d also like to thank Alicia Darnell, who has helped me with her thoughtful approach to science and editing. All of the members of the Vander Heiden lab, not just those that I have mentioned here, have taught me so much, and I truly could not have asked for a better set of people to work with. I had the opportunity to work with two incredible undergraduates during my PhD. Emma Gong worked in the lab throughout most of her time as an undergraduate, and it was such a rewarding experience to watch her develop. Emma’s ability to cut to the heart of a topic and identify the important questions always pushed me to be the best mentor and scientist that I could be. I was also fortunate to work with Montana Reilly, who is one of the most intelligent, hard-working people that I know. Much of the work in this dissertation would not have been possible without Montana’s contributions. Beyond their abilities as scientists, Emma and Montana are both a joy to work with and I always look forward to talking with them. They are two of the brightest people that I know, and I am excited to see what they do next. I would like to thank my undergraduate advisor Karen Arndt, as well as Kristin Klucevsek, the graduate student who served as my first scientific mentor. I learned so much in the Arndt lab about how to approach science, and the lessons that I learned in that environment have been critical throughout my time in graduate school. Finally, I’d like to thank my parents, Katie, Lauren, and my friends both in and out of lab for their constant love and support. I am very fortunate to have all of you. 5 TABLE OF CONTENTS ABSTRACT ................................................................................................................................................... 3 ACKNOWLEDGEMENTS ............................................................................................................................ 4 TABLE OF CONTENTS ...............................................................................................................................
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