Examining the impact of the obesity-inflammation axis on cancer by genomic and transcriptomic profiling

通过基因组和转录组分析检查肥胖-炎症轴对癌症的影响

• 批准号: 9767517
• 负责人: Yun Rose Li
• 金额: $ 6.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-18 至 2021-07-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767517
• 关键词: Address; Affect; Aging; Automobile Driving; Backcrossings; Biological; Body mass index; Caloric Restriction; Cancer Cell Growth; Cancer Model; Cancerous; Candidate Disease Gene; Carcinogen exposure; Carcinogens; Carcinoma; Cell Aging; Cell Proliferation; Cells; Chronic; Clinical; Collaborations; Complex; Cytokine Signaling; DNA Repair; DNA Sequence Alteration; Data; Defect; Development; Diagnosis; Diet; Dietary Fats; Dietary intake; Epithelial; Etiology; Exposure to; Expression Profiling; Female; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gene Expression Alteration; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Models; Genetic Transcription; Genome; Genomics; Heterogeneity; High Fat Diet; Human; Immune; Immune response; Impairment; Inflammation; Inflammatory Response; Institutes; Insulin; Interleukin-1; Interleukin-12; Interleukin-6; Intervention; Lead; Leptin; Link; Malignant Neoplasms; Maps; Measures; Mediating; Metabolic; Modeling; Molecular; Mus; Mutation; Obesity; Obesity associated cancer; Oncogenic; Oxidative Stress; Papilloma; Patients; Pattern; Process; Production; Proliferating; Public Domains; Quantitative Trait Loci; Reactive Oxygen Species; Receptor Gene; Reporter; Risk; Rodent Model; Role; Sampling; Signal Pathway; Signal Transduction; Skin Cancer; Skin Neoplasms; Solid; Solid Neoplasm; Somatic Mutation; Squamous cell carcinoma; Stem cells; Stimulus; Stromal Cells; Testing; Therapeutic; Time; Tissues; Tumor-infiltrating immune cells; Ultraviolet Rays; United States; Up-Regulation; Work; adipokines; adiponectin; cancer biomarkers; cancer cell; cancer diagnosis; cancer genome; cancer genomics; cancer stem cell; cell type; cigarette smoke; dietary restriction; experimental study; genetic signature; genome analysis; genome sequencing; human cancer mouse model; immune function; leptin receptor; male; mouse genome; mouse model; multiple omics; neoplastic cell; oxidative damage; response; tool; transcriptome sequencing; transcriptomics; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis; whole genome

Project Abstract: Obesity is associated with over 630,000 (40%) of all new cases of malignant neoplasms diagnosed annually in the United States1, and a high body mass index (BMI) increases the risk of over seventeen types of solid tumors2. Mounting evidence suggests that in addition to promoting cell proliferation, obesity may also drive the development of cancer by creating a state of chronic inflammation. Moreover, adiposity and high fat diet (HFD) has been shown to promote reactive oxidative stress (ROS) and impede normal immune function. Recent pan-cancer analyses have identified somatic mutation signatures associated with specific etiologies that promote cancer, such as cigarette smoke, UV radiation, defects in DNA repair, aging and possibly, inflammation. The genomic and functional impact of obesity, and its connection to inflammation, have not been well-elucidated in humans due to complex genetic and environmental heterogeneity. Previous work by our lab and others has identified carcinogen and ROS-related mutation signatures in mouse models of human cancers. In addition, using an interspecific backcross mouse model of skin cancer, we identified quantitative-trait loci (QTL) linked to high BMI, increased papilloma burden and progression to carcinomas. A significant female-specific QTL was centered on the leptin receptor gene (LEPR), whose expression is strongly correlated with genes enriched for cytokine signaling and immune response. Here, using established models of genetic and dietary obesity in mice, I will investigate possible mechanisms by which obesity or HFD can promote cancer. First, I will test the hypothesis that obesity mediates a chronic inflammatory response that promotes cancer by creating patterns of somatic mutation signatures consistent with excess ROS production, advanced cellular aging, or impaired DNA repair by determining with whole-genome sequencing if there is evidence of an obesity-associated genomic tumor mutation signature. Next I will test the hypothesis that obesity promotes upregulation of adipokine signaling pathways in tumors and stromal cells and induces transcriptomic signatures of inflammation in tumor-infiltrating immune cells. Finally, I will evaluate if dietary obesity affects the proliferation or development of cancer stem cells by performing lineage tracing using an inducible-Cre reporter mouse expressing LGR6, a stem cell marker of carcinomas in epithelial tissues. Together, using state-of-the-art multi-omic, computational and molecular tools, these aims will evaluate the role of the obesity-inflammation axis in promoting cancer and identify candidate genetic, functional and developmental targets for downstream mechanistic studies and therapeutic avenues.

项目摘要： 肥胖症与630，000例（40%）新诊断的恶性肿瘤病例有关 在美国，高体重指数（BMI）会增加17岁以上的风险。 实体瘤的类型2.越来越多的证据表明，除了促进细胞增殖， 肥胖也可能通过产生慢性炎症状态来推动癌症的发展。此外，委员会认为， 肥胖和高脂饮食（HFD）已显示促进反应性氧化应激（ROS）， 阻碍正常免疫功能。最近的泛癌症分析已经确定了体细胞突变 与促进癌症的特定病因相关的特征，如香烟烟雾，紫外线 辐射，DNA修复缺陷，衰老，可能还有炎症。基因组和功能的影响 肥胖及其与炎症的联系在人类中尚未得到很好的阐明， 遗传和环境异质性。我们实验室和其他人以前的工作已经确定了致癌物质 和ROS相关的突变特征。此外，使用 在皮肤癌的种间回交小鼠模型中，我们确定了与以下基因连锁的数量性状基因座（QTL）： 高BMI、乳头状瘤负荷增加和进展为癌。一个显著的雌性特异性QTL 以瘦素受体基因（LEPR）为中心，其表达与基因密切相关 富含细胞因子信号传导和免疫应答。在这里，使用已建立的遗传和 在小鼠的饮食性肥胖中，我将研究肥胖或HFD促进 癌首先，我将检验肥胖介导慢性炎症反应的假设， 通过创造与过量ROS一致的体细胞突变特征模式来促进癌症 生产，先进的细胞老化，或受损的DNA修复，通过确定与全基因组 如果存在肥胖相关的基因组肿瘤突变特征的证据，则进行测序。接下来我会 检验肥胖促进肿瘤中脂肪因子信号通路上调的假设， 基质细胞并诱导肿瘤浸润免疫细胞中炎症的转录组学特征。 最后，我将评估饮食性肥胖是否会影响癌症干细胞的增殖或发展， 使用表达干细胞标志物LGR 6的诱导性Cre报告小鼠进行谱系追踪 上皮组织中的癌。同时，使用最先进的多组学，计算和 分子工具，这些目标将评估肥胖-炎症轴在促进癌症中的作用 并确定下游机制的候选遗传、功能和发育靶点 研究和治疗途径。