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Genetic Screening Approaches to Cancer Driver Characterization and Synthetic Lethal Target Discovery

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Genetic Screening Approaches to Cancer Driver Characterization and Synthetic Lethal Target Discovery Genetic Screening Approaches to Cancer Driver Characterization and Synthetic Lethal Target Discovery The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Mengwasser, Kristen Elizabeth. 2018. Genetic Screening Approaches to Cancer Driver Characterization and Synthetic Lethal Target Discovery. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:41121232 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Genetic Screening Approaches to Cancer Driver Characterization and Synthetic Lethal Target Discovery A dissertation presented by Kristen Elizabeth Mengwasser to The Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Biological and Biomedical Sciences Harvard University Cambridge, Massachusetts May 2018 © 2018 Kristen Elizabeth Mengwasser All rights reserved. Dissertation Advisor: Dr. Stephen J Elledge Kristen Elizabeth Mengwasser Genetic Screening Approaches to Cancer Driver Characterization and Synthetic Lethal Target Discovery Abstract Advances in genetic screening technology have expanded the toolkit for systematic perturbation of gene function. While the CRISPR-Cas9 system robustly probes genetic loss-of-function in mammalian cells, a barcoded ORFeome library offers the opportunity to systematically study genetic gain-of-function. We employed these two screening tools for three purposes. First, we performed shRNA and CRISPR-based screens for synthetic lethality with BRCA2 deficiency, in two pairs of BRCA2 isogenic cell lines. BRCA2 mutation commonly drives hereditary breast and ovarian cancer, but also creates vulnerability to PARP inhibitor treatment. Among other genes, we found the AP endonuclease APEX2 and the flap endonuclease FEN1 to be synthetic lethal with BRCA2 deficiency; the base excision repair (BER) pathway was synthetic lethal overall. We demonstrated that FEN1 plays a role in microhomology-mediated end joining (MMEJ) and that a FEN1 inhibitor selectively targets BRCA-deficient cells, offering therapeutic potential in the setting of PARP inhibitor resistance. Second, we screened a barcoded ORFeome library for genes that either upregulate PD-L1 or interfere with IFNγ signaling. Tumor-expressed PD-L1 engages PD-1 on T cells, dampening T-cell based immune responses to tumors, while defects in iii IFNγ signaling underlie resistance to immunotherapy. We found 12 GPCRs that significantly increase cell surface PD-L1 display, including three LPARs (LPAR1/2/5), and a family of RNA-binding proteins (CELF3/4/5) that upregulates PD-L1. Conversely, we showed that CLK2 overexpression antagonizes IFNγ signaling; CLK2 is known to phosphorylate PTPN1 and is amplified in tumor types that respond poorly to immunotherapy. Thus, segregating patients based on CLK2 amplification status or augmenting immunotherapy with CLK2 inhibitors may improve clinical responses. Finally, we utilized CRISPR and ORF-based libraries targeting known and predicted tumor suppressor genes (TSGs) or oncogenes (OGs) to systematically screen cancer drivers for a variety of phenotypes. We found at least 20 genes not commonly annotated as drivers that enhanced proliferation, including PAWR, AMBRA1, and USP28. We screened OGs bearing tumor-associated point mutations and functionally validated the MYCN P44L mutation. We mapped drivers across multiple hallmark cancer phenotypes and found that IRF6 knockout promotes anoikis bypass. Thus, functional studies can augment computational approaches in identifying cancer driver genes. iv Table of Contents Chapter 1: Introduction ........................................................................ 1 I. Drivers of Tumorigenesis ................................................................................. 1 Genomic Alterations Drive Cancer ....................................................................................................... 1 Taking a Census of Cancer Drivers ...................................................................................................... 4 Drivers of Hereditary Breast and Ovarian Cancer ............................................................................... 7 II. Hallmarks of Cancer ....................................................................................... 10 Hallmark Properties and Stress Phenotypes of Cancer ...................................................................... 10 Genomic Instability Fuels Tumor Evolution ...................................................................................... 12 The DNA Damage Response (DDR) .................................................................................................. 15 Tumor Neoantigens and the Antitumor Immune Response ............................................................... 19 III. Challenges and Paradigms in Cancer Therapeutics ....................................... 21 Opening a Therapeutic Window ......................................................................................................... 21 Acquired Resistance to Targeted Therapies ....................................................................................... 23 The Promise of Immunotherapy ......................................................................................................... 26 Chapter 2: Genetic Screens Reveal APEX2 and FEN1 as BRCA2 Synthetic Lethal Targets ................................................................................... 30 I. Introduction ................................................................................................... 31 II. Results ............................................................................................................ 34 shRNA and CRISPR screens identify B2SL Candidates .................................................................... 34 Loss of early HR components promotes growth of cells with BRCA2 truncation mutations ............. 42 BRCA2 mutant cells rely on ATR activation and base excision repair ............................................. 45 AP endonuclease APEX2 is synthetic lethal with BRCA1 and BRCA2 loss-of-function ................... 48 Flap endonuclease FEN1 is a novel B2SL that plays a role in MMEJ .............................................. 53 III. Discussion ....................................................................................................... 59 IV. Methods .......................................................................................................... 63 Cell culture ......................................................................................................................................... 63 Lentivirus and retrovirus production and titering .............................................................................. 64 Generation of isogenic cell lines .......................................................................................................... 65 shRNA screens .................................................................................................................................... 65 CRISPR screens .................................................................................................................................. 67 Multicolor Competition Assay (MCA) ............................................................................................... 68 Western blotting ................................................................................................................................. 70 Immunofluorescence ............................................................................................................................ 71 Rescue Experiment ............................................................................................................................. 72 Dual EJ Reporter Assay ..................................................................................................................... 73 Chapter 3: Genome-Scale ORFeome Screen Identifies Regulators of PD-L1 Expression and IFNγ Signaling ........................................................... 75 I. Introduction ................................................................................................... 75 II. Results ............................................................................................................ 80 Optimization and design of two parallel genome-scale ORFeome screens .......................................... 80 v A genome-scale ORFeome screen identifies positive regulators of PD-L1 cell surface expression ...... 83 GSEA highlights GPCR signaling as positively regulating PD-L1 ..................................................... 90 CELF3 is a positive regulator of PD-L1 expression that is amplified in lung cancer ......................... 95 SPDYE2/4 or CLK2 Overexpression Interferes with IFNγ Signaling ............................................... 100 III. Discussion ..................................................................................................... 104 IV. Methods ........................................................................................................ 107 Cell culture .......................................................................................................................................
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