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Glutaminolysis: a Hallmark of Cancer Metabolism by Lifeng Yang

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Glutaminolysis: a Hallmark of Cancer Metabolism by Lifeng Yang ABSTRACT Glutaminolysis: A Hallmark of Cancer Metabolism by Lifeng Yang The goals of these projects are to study the critical role of glutamine (Gln) in ovarian cancer growth, metastasis, drug resistance and sources of glutamine in tumor microenvironment. 1): Gln‐addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. 1): we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low‐invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high‐invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients’ microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high‐invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting low‐invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs. 2): Reactive stromal cells are an integral part of tumor microenvironment (TME) in tumors and interact with cancer cells to regulate their growth and survival. Although targeting stromal cells could be a viable therapy to regulate the communication between TME and cancer cells, identification of stromal targets which make cancer cells vulnerable has remained challenging and still elusive. Here, we identify a previously unrecognized mechanism whereby metabolism of reactive stromal cells is reprogrammed through upregulated glutamine anabolic pathway. This dysfunctional stromal metabolism confers atypical metabolic flexibility and adaptive mechanisms in stromal cells allowing them to harness carbon and nitrogen from noncanonical sources to synthesize glutamine in nutrient-deprived conditions existing in TME. We demonstrate that targeting cancer associated fibroblasts (CAFs), a major component of reactive stroma that expresses high glutamine synthetase (GLUL), disrupts metabolic crosstalk between stromal and cancer cells. Our work underscores reliance of cancer cells on CAFs and presents a synthetic lethal approach to target tumor stroma and cancer cells simultaneously for desirable therapeutic outcomes. Acknowledgments First and foremost, I would like to express my thankfulness to my thesis advisor Dr. Deepak Nagrath for his scientific guidance for my PhD study. He is always so patient with me and teach me not only how to pursue my career and also my life. Because of his care, work, support, and communications with me, I get what I need for my future career and life. I really appreciate that he always makes projects better and better, and dig our potential to achieve higher and higher. Thanks to the freedom that he gave me, and always back me up! I would like to thank to my thesis committee: Dr. Zygourakis, Dr. Bennett, Dr. Marini for their advice during my thesis proposal and support on my PhD defense. Thanks to my lab colleagues. Christine and I worked at same project for nitric oxide effect on Warburg effect, and it was a great opportunity that she gave. Bahar and I worked together in lab for more than 5 years, and she was nice for many suggestions. Thanks to Hongyun’s care and support in lab and her efforts in my first project. Thanks to Joelle, always taking care of lab, and collaborating with me for different projects. Thanks to Abhinav, who really offers great help to teach me about data analysis, modify my paper, and work together for different projects. Thanks to my other previous labmates: Nadege, Thasni, Aaron. A special acknowledgement goes to my collaborators. Without them, all my works cannot go further and complete. Thanks to Tyler, Mangala, Dahai, Tsz-Lun (So), Cecil, Imelda, and their advisor Drs. Ram, Sood, Mok, Lu, Liu, v and Dr. Marini. They are always ready to help me with experiments set up, design and I learn a lot from discussion with them. Thanks to Dr. Chacko and Daniel’s help for GCMS and LCMS machine and troubleshooting. I thanks to my hard working undergraduates and high school student. Stephen helped me with setting up experiments and developed protocols. Julia and Sun Hye were so careful for all experiments she performed and got perfect data. Katherine and Lisa were so nice, diligent and always ready to offer help when I needed. Thanks to the help from Joseph and Ryuichi for my CAFs project and continuous work. Thanks to Pavan and Josh’s help for all the works that they do. Thanks to undergraduates and high school students’ help during summer holidays. Their joining brought a lot of energy and happiness to our lab! I would like to thank the amazing staff in our department: Barbara, Ania, Leewanda, Karen and Pam. Thanks to other department professors for their help in my courses and my PhD qualify presentation. Thanks to CHBE GSA’s host of different events. I would like to thank my friends with their advice, and their time we hanged out and played together. Their care enriched my life. Thanks to my family for their support and respect on my own decision, and give me freedom to let me pursue what I am interested. Both my father and mother set life example for me to follow. I have witnessed them working from day to night in order to create a little more and a little more for our living expense. It is a great study environment that they build up, and expand using their selfish love vi and “never-give up” efforts, so I can learn what I want without any distraction. I Love you, Dad (Mr. Yang), and Mom (Mrs. Shen). I thank my grandma, hoping she is happy in heaven, and my grandpa, hoping he can have a happy life. Thanks to all people I love and love me! Contents Acknowledgments ................................................................................................ iv Contents ................................................................................................................ vii List of Figures ........................................................................................................ xi List of Tables ........................................................................................................ xiv List of Equations ................................................................................................... xv Nomenclature ......................................................................................................... 1 Introduction ............................................................................................................. 5 1.1. Ovarian Cancer ..................................................................................................... 5 1.2. Glutaminolysis: Hallmark of Cancer Metabolism ............................................. 6 1.2.1. Oncogenic and microenvironment regulation of Gln metabolism .......... 7 1.2.2. Glutaminolysis: supporting rapid cell proliferation beyond carbon provision ................................................................................................................... 10 1.2.3. Gln Induces Cell Signaling Affecting Cell proliferation, Apoptosis and Drug Resistance ...................................................................................................... 18 1.2.4. Gln Sources .................................................................................................. 19 1.2.5. Assessing Gln Uptake and Metabolism in vivo ....................................... 24 1.2.6. Drug Application targeting Gln Metabolism ............................................. 25 Metabolic shifts towards glutamine regulates tumor growth, invasion and bioenergetics in ovarian cancer ......................................................................... 26 2.1. Glutamine dependence in ovarian cancer cells is correlated with cancer invasiveness and patient survival ............................................................................ 27 2.2. Glutamine differentially increases TCA cycle metabolite abundances, in high-invasive versus low-invasive ovarian cancer cells ....................................... 35 2.3. High-invasive cells are glutamine dependent for increased respiration, proliferation, and redox balance ............................................................................... 45 2.4. Ratio of Glutamine Catabolism over Anabolism Correlates with Invasiveness ................................................................................................................ 53 2.5. Clinical significance of glutamine catabolism and therapeutic effectiveness of GLS1 siRNA in ovarian cancer models .............................................................. 58 viii 2.6. Glutamine regulates cancer cell Invasiveness through STAT3 activity in high-invasive ovarian cancer cells ........................................................................... 61 2.7. Glutamine dependent anaplerosis regulates glycolysis in high-invasive cancer cells through STAT3 phosphorylation ........................................................ 69 2.8. Discussion ...........................................................................................................
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