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I Genetic Determinants of Cancer Cell Survival in Tumor Genetic Determinants of Cancer Cell Survival in Tumor Microenvironment Stresses by Melissa Marie Keenan University Program in Genetics and Genomics Duke University Date:_______________________ Approved: ___________________________ Jen-Tsan Ashley Chi, Supervisor ___________________________ Jack Keene ___________________________ James Koh ___________________________ Deborah M. Muoio ___________________________ Jeffrey Rathmell Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the University Program in Genetics and Genomics in the Graduate School of Duke University 2015 i v ABSTRACT Genetic Determinants of Cancer Cell Survival in Tumor Microenvironment Stresses by Melissa Marie Keenan University Program in Genetics and Genomics Duke University Date:_______________________ Approved: ___________________________ Jen-Tsan Ashley Chi, Supervisor ___________________________ Jack Keene ___________________________ James Koh ___________________________ Deborah M. Muoio ___________________________ Jeffrey Rathmell An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the University Program in Genetics and Genomics in the Graduate School of Duke University 2015 i v Copyright by Melissa Marie Keenan 2015 Abstract In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. Additionally, cancer cells exposed to these stresses are more resistant to therapies, more likely to metastasize and often are worse for patient prognosis. While the presence of these stresses is generally negative for cancer patients, since these stresses are mostly unique to the TME, they also offer an opportunity to develop more selective therapeutics. If we achieve a better understanding of the adaptive mechanisms cancer cells employ to survive the TME stresses, then hopefully we, as a scientific community, can devise more effective cancer therapeutics specifically targeting cancer cells under stress. To systematically identify genes that modulate cancer cell survival under stresses, we performed shRNA screens under hypoxia or lactic acidosis. From these screens, we discovered that genetic depletion of acetyl-CoA carboxylase alpha (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis. Furthermore, the loss of ACLY or ACC1 reduced the levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia- induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while α-ketoglutarate levels decrease under hypoxia in control cells, α- iv ketoglutarate was paradoxically increased under hypoxia when ACC1 or ACLY were depleted. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4, likely via an epigenetic mechanism. Therefore, ACC1 and ACLY regulated the levels of ETV4 under hypoxia via increased α-ketoglutarate. These results reveal that the ACC1/ACLY-α-ketoglutarate- ETV4 axis is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future. v Contents Abstract ......................................................................................................................................... iv List of Tables .................................................................................................................................. xi List of Figures .............................................................................................................................. xii Acknowledgements ................................................................................................................... xiv 1. Introduction ................................................................................................................................ 1 1.1 Tumor Cells ........................................................................................................................ 3 1.2 Stresses of the TME ........................................................................................................... 4 1.2.1 Glucose limitation ........................................................................................................ 5 1.2.2 Amino acid limitation ................................................................................................. 7 1.2.3 Biophysical or mechanical stresses ............................................................................ 8 1.2.4 Lactic Acidosis ............................................................................................................ 10 1.2.5 Oxygen limitation (hypoxia) .................................................................................... 14 1.3 Functional genomics through RNA interference screens ......................................... 22 1.3.1 Introduction ................................................................................................................ 22 1.3.2 Designing an RNAi screen experiment .................................................................. 22 1.3.3 Advantages and Disadvantages of RNAi screens ................................................. 26 1.3.4 Previous applications to cancer and the TME stresses ......................................... 29 1.4 Overview of Chapters .................................................................................................... 33 2. Positive Selection Screen under Lactic Acidosis ................................................................. 35 2.1 Introduction ..................................................................................................................... 35 vi 2.2 Methods ............................................................................................................................ 36 2.2.1 Positive Selection Screen ........................................................................................... 36 2.2.2 Cell culture, TME stress treatments and generation of stable shRNA cell lines ............................................................................................................................................... 38 2.2.3 Crystal violet staining ............................................................................................... 39 2.2.4 Determination of cell number .................................................................................. 39 2.2.5 Flow cytometry ........................................................................................................... 39 2.2.6 Protein lysate collection and Western blots ........................................................... 40 2.2.7 Quantitative real-time PCR ...................................................................................... 40 2.3 Initial Results ................................................................................................................... 41 2.4 Validation of Results ....................................................................................................... 43 2.4.1 SEL1L ........................................................................................................................... 45 2.4.2 RNF123 ........................................................................................................................ 49 2.4.3 LIMD1 .......................................................................................................................... 52 2.4.4 Other candidates of interest ..................................................................................... 56 2.5 Future considerations ..................................................................................................... 57 3. Genome-wide Functional Genomic Screens under Hypoxia and Lactic Acidosis ........ 58 3.1 Introduction ..................................................................................................................... 58 3.2 Methods ............................................................................................................................ 59 3.2.1 Genome-wide pooled shRNA screen ...................................................................... 59 3.2.2 Cell culture, TME stress treatments and generation of stable shRNA cell lines ............................................................................................................................................... 62 3.2.3 Crystal violet staining ............................................................................................... 63 vii 3.2.4 Determination of cell number .................................................................................. 63 3.2.5 Flow cytometry ........................................................................................................... 64 3.2.6 Protein lysate collection and Western blots ..........................................................
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