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A Next-Generation Functional Genomics Strategy to Deconvolute Compound

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A Next-Generation Functional Genomics Strategy to Deconvolute Compound A next-generation functional genomics strategy to deconvolute compound genetic drivers and genotype-to- phenotype relationships in bladder cancer 2019 Eula and Donald S. Coffey Innovative Research Award Finalist John K. Lee, M.D., Ph.D.; Assistant Member, Human Biology Division, Fred Hutchinson Cancer Research Center Alicia Wong; Human Biology Division, Fred Hutchinson Cancer Research Center, Huiyun Sun; Human Biology Division, Fred Hutchinson Cancer Research Center, Sujata Jana, Ph.D.; Human Biology Division, Fred Hutchinson Cancer Research Center, Andrew C. Hsieh, M.D.; Assistant Member, Human Biology Division, Fred Hutchinson Cancer Research Center A next-generation functional genomics strategy to deconvolute compound genetic drivers and genotype-to-phenotype relationships in bladder cancer Authors: Alicia Wong, Huiyun Sun, Sujata Jana, Andrew C. Hsieh, John K. Lee Author Affiliations: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA Background: Next-generation sequencing has uncovered the sheer genomic heterogeneity of bladder cancer. Current approaches to model tumorigenesis are poorly suited for the systematic functional interrogation of the diverse, higher-order genetic interactions that drive bladder cancer due to the lack of scale, throughput, and economy. Methods We are developing a strategy to address this issue by leveraging organoid cultures, multiplex transduction with a barcoded lentiviral library of genetic perturbations, in vivo selection for tumorigenesis, and digital profiling of resultant tumors by single-cell sequencing. We initiated bladder urothelial organoids from basal cells (Lin- EpCAM+CD49fhigh) isolated from C57BL/6J bladders. A lentiviral library was constructed that encodes gain- and loss-of-function genetic events recapitulating recurrent alterations in bladder cancer. Each vector contains matching 10-nucleotide barcodes at the 5’ and 3’ ends. Cells were transduced by mixing lentivirus into cell- Matrigel suspensions prior to seeding of organoid culture droplets. Organoids were transplanted subcutaneously into the flanks of NSG mice. Targeted single-cell DNA sequencing on the Mission Bio Tapestri platform was performed to recover compound lentiviral barcodes from tumor cells. Results: Bladder urothelial cells were transduced in organoid culture with lentivirus to achieve viral copy numbers (VCN) of up to 20 with a linear relationship between VCN and lentiviral dose. Barcoded lentiviruses encoding mutant PIK3CA E545K, mutant FGFR3 S243C, PVRL4, PPARG, and YWHAZ generated a squamous cell carcinoma phenotype within our mouse bladder urothelial tumorigenesis assay. Single-cell characterization of ~3,000 tumor cells from this model showed the co-existence of multiple clonal populations driven by distinct combinations of oncogenic drivers. Conclusions: We achieved efficient lentiviral transduction of bladder urothelial cells to enable the interrogation of higher- order genetic interactions in cancer initiation. Genetic heterogeneity can be introduced via the Poisson distribution of lentiviral transduction and sensitively recovered by massively parallel targeted scDNA-seq of lentiviral barcodes. With this approach, we have generated genetically-defined models of bladder cancer and provide preliminary proof-of-principle for a strategy to rapidly deconvolute complex genotype-to-phenotype relationships in bladder cancer initiation. Myeloid-Derived Suppressor Cells Inhibit T Cell Activation in Prostate Cancer through Nitrating LCK 2019 Eula and Donald S. Coffey Innovative Research Award Finalist Xin Lu, Ph.D., Boler Assistant Professor, University of Notre Dame; Indiana University Shan Feng, Ph.D., Postdoctoral Fellow, Liang Cheng, M.D., Virgil Moon Professor of Pathology Myeloid-Derived Suppressor Cells Inhibit T Cell Activation in Prostate Cancer through Nitrating LCK Xin Lu, Ph.D., Boler Assistant Professor, University of Notre Dame; Indiana University Shan Feng, Ph.D., Postdoctoral Fellow, Liang Cheng, M.D., Virgil Moon Professor of Pathology Background: Patients with advanced prostate cancer (PCa) benefit from androgen deprivation therapy initially, but often later develop lethal metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint blockade (ICB) using antibodies against CTLA4 or PD1/PD-L1 generates durable therapeutic responses in a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to ICB. Our previous publications established that myeloid- derived suppressor cells (MDSCs) are the key player in PCa immune evasion, and targeting MDSCs with multikinase inhibitors or CXCR2 inhibitors could synergize with ICB to elicit potent anti-mCRPC effect (Cancer Discovery, 2016; Nature, 2017). More effective and specific MDSC inhibition relies on deeper mechanistic understanding of MDSCs. One main mechanism for MDSCs to induce T cell tolerance is through secretion of reactive nitrogen species (RNS, e.g. peroxynitrite). However, this mechanism remains poorly understood and very few nitrated proteins are known. Methods: We developed a new nitroproteomic approach for the identification of nitropeptides from cells and tissues (JoVE. 2019. PMID: 31259896). The biological models we used for target identification and functional validation are Pten/p53/Smad4 PCa transgenic model and syngeneic Lewis Lung Carcinoma (LLC) model. Results: We identified that lymphocyte-specific protein tyrosine kinase (LCK), an initiating tyrosine kinase in the T cell receptor signaling cascade, is nitrated at Tyr394 by MDSCs. LCK nitration inhibited T cell activation, leading to reduced interleukin-2 production and proliferation. In human T cells with defective endogenous LCK, wild type, but not nitrated LCK, rescued IL2 production. We documented elevated 3-nitrotyrosine signals in clinical samples of CRPC. In both the Pten/p53/Smad4 mCRPC model and LLC model, we showed that ICB therapy (PD1 and CTLA4 antibody cocktail) elicited strong anti-tumor efficacy when combined with a RNS neutralizing agent. Conclusions: We have identified a previously unknown mechanism of T cell inactivation by MDSC-induced protein nitration and illuminated a clinical path hypothesis for combining ICB with RNS-reducing agents in the treatment of mCRPC (Figure 1). Figure 1. Schematic showing the mechanism of LCK-Y394 nitration by MDSC-derived RNS. First Genetically Engineered Mouse Model of Penile Cancer and Its Application in Preclinical Immunotherapy Xin Lu, Ph.D., Boler Assistant Professor, University of Notre Dame; Indiana University Tianhe Huang, PhD, Postdoctoral Fellow, Pheroze Tamboli, MBBS, Professor, MD Anderson Cancer Center, Priya Rao, MD, Associate Professor, MD Anderson Cancer Center, Magaly Martinez Ferrer, PhD, Assistant Professor, University of Puerto Rico, Ronald A. DePinho, MD, Professor, MD Anderson Cancer Center, Curtis A. Pettaway, MD, Professor, MD Anderson Cancer Center First Genetically Engineered Mouse Model of Penile Cancer and Its Application in Preclinical Immunotherapy Xin Lu, Ph.D., Boler Assistant Professor, University of Notre Dame; Indiana University Tianhe Huang, PhD, Postdoctoral Fellow, Pheroze Tamboli, MBBS, Professor, MD Anderson Cancer Center, Priya Rao, MD, Associate Professor, MD Anderson Cancer Center, Magaly Martinez Ferrer, PhD, Assistant Professor, University of Puerto Rico, Ronald A. DePinho, MD, Professor, MD Anderson Cancer Center, Curtis A. Pettaway, MD, Professor, MD Anderson Cancer Center Background: Penile cancer is a rare but highly morbid disease, with penile squamous cell carcinoma (PSCC) accounting for over 95% of all cases. PSCC often results in devastating disfigurement and only half of the patients survive beyond 5 years. The molecular etiology of PSCC remains poorly understood, which causes limited treatment options for advanced tumors incurable with surgery or radiotherapy alone. Methods: Herein, we describe the development of the first genetically engineered mouse (GEM) model of PSCC. Transcriptomics of the penile tumor and normal penile epithelium was profiled by RNA-seq for mechanistic investigation and comparison to human penile cancer transcriptomics. Immunophenotyping of the model was performed by CyTOF. The model was subjected to unbiased molecular annotation with RPPA and inhibitor screening for potential novel drugs against PSCC. Pharmacological targeting of the tumor microenvironment was combined with immune checkpoint blockade antibodies (PD1, CTLA4) for the discovery of new treatment strategy of lethal PSCC. Results: The GEM model is highly relevant to the human disease by virtue of sharing up- and down-regulated genes and pathways with human PSCC based on comparative transcriptomic and biomarker analyses. In silico and animal experiments elucidated both cancer cell-intrinsic (β-catenin and SOX2 transcription activation) and extrinsic (COX2-dependent inflammatory microenvironment) mechanisms that were operative to drive the progression of PSCC. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. Drug screen studies informed by targeted proteomics identified a few potential therapeutic strategies for PSCC. Conclusion: Our studies have established what we believe to be essential resources for studying PSCC biology and developing new therapies (Figure 1). Figure 1. First Genetically Engineered
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