Role of the Oral Microbiome in Oral Squamous Cell Carcinoma Progression

口腔微生物组在口腔鳞状细胞癌进展中的作用

• 批准号: 9975819
• 负责人: PHILIP Stashenko
• 金额: $ 16.47万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-10 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975819
• 关键词: Address; Antibiotic Therapy; Antibodies; Bacteria; C57BL/6 Mouse; Cancer cell line; Carcinogens; Cell Proliferation; Cellular Assay; Chronic; Colon; Communities; Coupled; Data; Development; Disease; Epithelial Cells; Exhibits; Exposure to; Fusobacterium nucleatum; Gallbladder; Gene Expression Profiling; Genes; Genetic Transcription; Gnotobiotic; Goals; Growth; Head and Neck Cancer; Helicobacter Infections; Human; Human Microbiome; Hyperactive behavior; Immune; Immune response; Immunity; Immunosuppression; Immunotherapeutic agent; Inflammation; Intervention; Lead; Leukocytes; Link; Lower Gastrointestinal Tract; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Mediating; Metabolic Pathway; Modality; Molecular; Mus; Myeloid-derived suppressor cells; Neoplasm Metastasis; Neoplastic Cell Transformation; Oral; Oral cavity; Oxidative Stress; Oxides; Pasteurella pneumotropica; Pathogenicity; Pathway interactions; Phenotype; Play; Production; Recurrence; Regimen; Regulatory T-Lymphocyte; Reporting; Research; Role; Signal Transduction; Stomach; Survival Rate; Testing; Tongue; Transplantation; Tumor Cell Invasion; Tumor Immunity; Virulence; cancer survival; carcinogenesis; cell growth; cell transformation; draining lymph node; dysbiosis; gut microbiome; host microbiome; in vivo; insight; lymph nodes; malignant mouth neoplasm; malignant stomach neoplasm; metatranscriptomics; microbiome; mouse model; mouth squamous cell carcinoma; neoplastic cell; novel strategies; novel therapeutics; oral microbiome; outcome forecast; overexpression; pathobiont; pathogen; pathogenic bacteria; prevent; response; transcriptome sequencing; transcriptomics; tumor; tumor growth; tumor initiation; tumor microbiome; tumor progression; tumorigenesis; tumorigenic

Project Abstract Head and neck cancer represents the sixth most common malignancy worldwide, and oral squamous cell carcinomas (OSCC) are the most frequent malignancies in the oral cavity. Despite improvements in prognosis for many other human cancers, survival rates for OSCC have remained nearly unchanged for decades, emphasizing the urgent need for new treatment modalities. Mounting evidence indicates that the human microbiome plays a key role in promoting a variety of cancers, including stomach, colon and gall bladder, via various mechanisms. In contrast to the lower GI tract, the role of, and mechanisms by which, the oral microbiome may contribute to OSCC remain obscure. The impetus for this project is that gnotobiotic mouse models, coupled with functional transcriptomics, offer powerful new approaches to elucidate the mechanisms that underlie the tumorigenic effects of the oral microbiome in OSCC. In preliminary studies we found that germfree mice colonized with microbiomes, and challenged with the carcinogen 4-NQO, developed many more, and larger tumors than mice that remained germfree. Transcriptionally-hyperactive candidate pathogens were identified, which expressed numerous virulence signatures, paralleling previous findings in human OSCC. Tumor-infiltrating leukocytes (TIL) appeared to be modulated to an immunosuppressive vs protective phenotype in microbiome-colonized mice. These findings lead to our central hypothesis, that key pathogenic species in the oral microbiome promote OSCC progression, at least in part by inducing immunosuppression vs protective immunity. This will be tested by determining the transcriptionally-hyperactive species that most strongly promote the growth and metastasis of syngeneic mouse oral cancer (MOC) cell line orthografts in mouse tongues in vivo. Bacterial metabolic pathways will be characterized by metatranscriptomics, and the microbiome-modulated immune as well as tumor cell responses by RNASeq. Immune responses induced by tumorigenic pathogens will be characterized locally and in draining lymph nodes. The function of Treg and myeloid-derived suppressor cells will be evaluated by abrogation with immunotherapeutic antibodies in vivo. Direct effects of tumorigenic pathogens on tumor cell growth and invasion will be determined. The goal is to identify key oral tumorigenic bacteria and their molecular mechanisms that are responsible for promoting OSCC progression. Successful completion of this project will suggest new microbiome-focused interventions to reduce OSCC initiation and recurrence, and contribute to the development of next generation therapeutics for this recalcitrant and devastating disease.

项目摘要 头颈癌代表了全球第六大最常见的恶性肿瘤，口服鳞状细胞 癌（OSCC）是口腔中最常见的恶性肿瘤。尽管预后有所改善 对于许多其他人类癌症，OSCC的生存率几十年来一直保持不变， 强调迫切需要新的治疗方式。越来越多的证据表明人类 微生物组在促进各种癌症（包括胃，结肠和胆囊）中起关键作用， 各种机制。与较低的胃肠道相反，口头的作用和机制的作用和机制 微生物组可能有助于OSCC仍然晦涩。该项目的动力是Gnotobiotic Mouse 结合功能转录组学，模型提供了强大的新方法来阐明机制 这是OSCC口腔微生物组的致瘤作用。在初步研究中，我们发现 用微生物组殖民并用致癌4-NQO挑战的无毛发小鼠发展了许多 比保持无损的小鼠更多，更大的肿瘤。转录疗法的候选病原体 被鉴定出来，表达了许多毒力特征，与人类OSCC中的先前发现并行。 肿瘤浸润的白细胞（TIL）似乎是针对免疫抑制与保护性的 微生物组殖民化小鼠的表型。这些发现导致了我们的中心假设，即关键的致病性 口腔微生物组中的物种促进OSCC进展，至少部分通过诱导免疫抑制与 保护性免疫。这将通过确定大多数的转录高温物种来测试 强烈促进合成小鼠口腔癌（MOC）细胞系正骨移植的生长和转移 老鼠的舌头在体内。细菌代谢途径将以元文字组学为特征，并且 RNASEQ通过微生物组调节的免疫以及肿瘤细胞反应。免疫反应由 肿瘤病原体将在局部和排水淋巴结中进行表征。 Treg和 髓样衍生的抑制细胞将通过在体内废除免疫治疗抗体来评估。 肿瘤病原体对肿瘤细胞生长和浸润的直接影响。目标是 鉴定关键的口腔肿瘤细菌及其分子机制，这些机制负责促进 OSCC进展。该项目的成功完成将建议新的以微生物组为中心的干预措施 减少OSCC的启动和复发，并有助于开发下一代治疗剂 这种顽固和毁灭性疾病。