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Resistance Is Futile: Physical Science, Systems Biology and Single-Cell Analysis to Understanding the Plastic and Heterogeneous

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Resistance is Futile: Physical science, systems biology and single-cell analysis to understanding the plastic and heterogeneous nature of melanoma and their role in non- genetic drug resistance Thesis by Yapeng Su In Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2020 (Defended November 22, 2019) ii 2020 Yapeng Su ORCID: 0000-0002-6305-8467 iii ACKNOWLEDGEMENTS As I come close to the end of the Ph.D. chapter in my life, I look back on this unforgettable journey and feel thankful for the help and support of so many amazing people without whom I would not have been able to complete this thesis. I would like to especially mention some individuals. First and foremost, I would like to express my deepest gratitude to my primary advisor, Prof. James Heath, for having me in the lab and guiding and supporting me to explore the most cutting-edge science throughout my graduate study. He has given me an incredible amount of intellectual freedom to pursue my own research ideas and interest while always supporting me with unlimited resources and inspiring intellectual guidance throughout my scientific adventures. He, as an example of a great scientist and visionary leader, has indelibly enriched me and shaped my identity as a researcher. I feel lucky and proud to work with Jim and I could not imagine having a better advisor and mentor for my entire Ph.D. study. I also want to extend my heartfelt thanks to my thesis co-advisor, Prof. David Baltimore, and my academic co-advisor, Prof. Mark Davis. In the most difficult times of my Ph.D., both of them took me under their wings and provided me with lab space, important guidance, and support throughout my graduate study. My biology training from David and the Baltimore lab has been crucial for my Ph.D. research and for my training towards a mature scientist. David’s support, enthusiasm, and guidance for the physical science and engineering approaches that I utilize to understand biology have been critical to shaping my scientific career. David’s unlimited support and care for my career development have also been something I will always cherish. Mark also had very strong influence on my academic training, especially in the field of chemical engineering, which is the major for both my undergraduate and my Ph.D. degrees. I am grateful for his unwavering guidance and support for my career advancement. He has set a remarkable example of how chemical engineering approaches can shift the paradigm of biomedical fields and help people fight against cancer. He is the ideal role model of a chemical engineer whom I want to learn from in my future career. I also want to thank Prof. Zhen-Gang Wang and Prof. Dave Tirrell for taking the time to serve on my committee, providing me with research guidance, and being a part of my academic growth. Zhen-Gang is like one of my family: he cares about me as a person and iv provided me with guidance and encouragement throughout my entire graduate life. In addition, Zhen-Gang’s teaching really impressed me and set an example for how a great teacher should be. Dave has always been so nice to me in person and is willing to offer the most insightful points to guide my research. Many of his questions in my committee meetings are very critical and challenge me to grow as a better scientist and critical thinker. I have been extremely fortunate to have the great opportunity to work with many great scientists throughout my entire Ph.D. Dr. Wei Wei, Dr. Min Xue, and Dr. Guideng Li were my postdoc mentors when I first started working in the Heath and Baltimore labs. They taught me the basic skillset that set the foundations for many of my research projects. They all now have their own research groups in different universities, but I still have the opportunity to continue collaborating with them. I want to thank Prof. Antoni Ribas for introducing me to the non-genetic drug resistance problem in melanoma, which turned out to be the main theme of my Ph.D. thesis. He also taught me all of the relevant melanoma biology and guided me throughout all of my research projects. Prof. Raphael Levine is my computational analysis mentor; the surprisal analysis he invented and taught me has been the most beautiful computational tool used throughout most of my Ph.D. projects for scientific discovery within huge dimensions of data. I also want to thank my other senior collaborators from ISB, Stanford, and MIT, including Prof. Leroy Hood, Prof. Nathan Price, Prof. Nitin Baliga, Prof. Ilya Shmulevich, Prof. Sui Huang, Prof. Gary Nolan, Prof. Sylvia Plevritis, Prof. Aviv Regev, and Prof. Eric Lander for their support in many of the exciting collaborative projects. My heartfelt appreciation also goes to my lab mates in the Heath, Baltimore and the Davis groups, including Dr. Wei Wei, Dr. Min Xue, Dr. Jing Zhou, Dr. Songming Peng, Dr. Jun Wang, Dr. Jing Yu, Dr. Nataly Balasha, Dr. David Bunk, Dr. Jake Kim, Dr. Amy McCarthy, Dr. Jingxin Liang, Dr. Alex Xu, Dr. Alphonsus Ng, Dr. Yue Lu, Dr. Matt Idso, William Chour, Dan Yuan, Dr. Guideng Li, Dr. Alok Joglekar, Dr. Shuai Jiang, Dr. Mati Mann, Dr. Luke Frankiw, Michael Leonard, Dr. Emily Wyatt and Dr. Jong Hun Kevin Kang, Dr. Viktor Cybulskis, Dr Matthew Kale, and all other current and past members of the labs. I have the habit of working late nights in the lab, and was so fortunate to have the company of such a diverse group of people throughout different periods of my Ph.D.: when I started in the Heath lab at Caltech, Amy was always the person to keep me company during late nights in the lab, and she allowed me to use her “gaming computer” to analyze huge RNA-seq datasets for my research project; later on, when I moved to the Baltimore lab, I was lucky to have Luke be together with me when I worked late in the lab. Kevin is the one in the Davis lab who will v always make Chinese teas for me late at night; and now when I move to ISB, I have William, who stays late together with me working in the lab. Their company and support throughout my graduate journey across different labs and institutions is something that always warms my heart when I look back. I also want to give special thanks to many other Caltech faculties. Prof. Frances Arnold was my first mentor in Caltech when I did my first graduate-school rotation. She is the one who arranged my pickup from LAX when I first arrived in this new country far from home. She and her lab helped me adapt to life in the U.S. Although I did not end up joining her lab, I feel lucky to still have her guidance and advice for my future career development. Prof. Lu Wei (and her student Jiajun Du) has been such a great and supportive collaborator; I really enjoyed the beautiful science we discovered during our collaboration and I wish to continue working with her in my future academic career. Prof. Ellen Rothenberg and her student Xun Wang (and Xun’s wife Can Li) has been a great resource for me in the epigenomics fields, which is a critical part of my Ph.D. research. When I TA’d for Prof. Ismagilov, I learned how to be a well-planned and organized teacher. As the option representative of the chemical engineering department, Prof. Giapis has been a great resource for me throughout my graduate study and life. I would also like to acknowledge my undergraduate advisors Prof. Yingjin Yuan, Prof. Rongxin Su, and Prof. Zhimin He, who first got me into scientific research and gave me the tools I needed to pursue my Ph.D. One of the most fulfilling and unforgettable experience in my graduate school is to mentor young, hardworking, and talented undergraduate students. I was so fortunate to mentor and work with Jihoon Lee, Rachel Ng, Marcus Bintz, Gabe Dreiman, Anne Chen, Victoria Liu, Stephanie Wong, Jessica Wang, Kaitlyn Takata, Sarah Pack, and Daniel Chen. They all have made great contributions to my papers and I am so glad to see many of them now becoming Ph.D. or M.D. Ph.D. candidates in many top universities. My life in graduate school would not have been nearly as enjoyable without the many friends I met at Caltech, including but not limited to Dr. Xiaozhou Ruan, Dr. Qifan Yang, Dr. Shuai Wang, Xiawei Huang, Yandong Zhang, Xiaozhe Ding, Ronghui Zhu, Xun Wang, Can Li, Jiajun Du, Dr. Peng He, Dr. Haoqing Wang, Dr. Zixuan Shao, Chengcheng Fan, Yicheng Luo, Sheng Wang, Yitong Ma, Hanwei Liu, Weilai Yu, Shan Huang, Jiaming Li, Kai Chen, Kun Miao, Chenxi Qian, Xinyan Liu, Xinhong Chen, Ruohan Wang, Yalu Chen, Dr. Yufeng Huang, Dr. Yuanyue Liu, Dr. Sijia Dong, Dr. Jin Qian, Dr. Amy McCarthy, William Chour, vi Dr. Alphonsus Ng, Dr. Yue Lu, Dr. Matt Idso, Dr. Luke Frankiw, Dr. Alok Joglekar, Dr. Mati Mann, Dr. Emily Wyatt, Dr. Jong Hun Kevin Kang, Dmitriy Zhukov, Roberta Poceviciute, Ahmad Omar, Nick Porubsky, and many others. I would also like to thank every staff member of my labs, my department, and graduate office and international student program of Caltech, including but not limited to Elyse Garlock, Katrine Museth, Dazy Johnson, Rick Edmark, Theresa Davis, Katie Clark, Julie Kelly, Martha Hepworth, Allison Kinard, Kathy Bubash, Natalie Gilmore, Angelica Medina- Cuevas, Laura Flower Kim, and Daniel Yoder.
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