Oral Microbiota and Toll-Like Receptor Pathways in Head and Neck Cancer

头颈癌中的口腔微生物群和 Toll 样受体通路

• 批准号: 10063370
• 负责人: Daniel N Frank
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063370
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adaptor Signaling Protein; Address; Affect; Agonist; Anatomy; Antibiotics; Cancer Model; Catalytic Domain; Cell Line; Cell Wall; Clinical Trials; Colorectal Cancer; Complex; Data; Data Analyses; Data Set; Development; Diagnosis; Disease; Disease Outcome; Exhibits; Genes; Germ-Free; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Health; Human; Human Microbiome; Human papilloma virus infection; Immunity; Immunologics; Immunotherapy; In Vitro; Incidence; Inflammatory; Integration Host Factors; Intervention; Knowledge; Laboratories; Lactobacillus; Life; Link; Literature; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metabolism; Metagenomics; Microbiology; Mission; Molecular; Mouth Neoplasms; Mus; Oral; Oral cavity; Outcome Measure; PIK3CA gene; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Pharmacologic Substance; Prevention; Production; Public Health; Publications; Publishing; Receptor Gene; Receptor Signaling; Reporting; Research; Ribosomal RNA; Role; Shapes; Signal Pathway; Signal Transduction; Site; Smoking; Specimen; TLR1 gene; TLR2 gene; TLR6 gene; Technology; Testing; Therapeutic; Therapeutic Agents; Tobacco use; Toll-Like Receptor Pathway; Toll-like receptors; Translating; United States National Institutes of Health; Work; carcinogenicity; disability; drinking; dysbiosis; effective therapy; experimental study; gut microbiota; human disease; improved; in vivo; inhibitor/antagonist; innovation; knock-down; malignant mouth neoplasm; metabolomics; microbial; microbial host; microbiome; microbiome research; microbiota; microorganism; mouse model; novel; oral microbial community; outcome forecast; pre-clinical; response; targeted agent; targeted treatment; tool; transcriptome sequencing; translational impact; tumor

PROJECT SUMMARY Head and neck squamous cell carcinoma (HNSCC) remains a lethal disease despite concerted efforts to improve its diagnosis and treatment. Although smoking, drinking, and HPV infection are closely linked to HNSCC, emerging evidence also suggests that changes in the human microbiome are associated with HNSCC. However, little is known about how the altered microbiota affect HNSCC pathogenesis or its treatment. Currently, most studies linking the microbiome to cancer have focused on gut microbiota, which either contributes locally to colorectal cancer pathogenesis, or more broadly, modulates metabolism and immunity systemically. The oral cavity, which is more directly relevant to the local microenvironment in HNSCC, harbors one of the most complex and diverse microbiomes of all human anatomical sub-sites. However, how either the gut or oral microbiotas shape the local and systemic microenvironment in HNSCC pathogenesis and treatment are completely unknown. Our long-term goal is to determine the functional role(s) and mechanisms of action of the microbiome in HNSCC and to translate these findings into novel preventative and therapeutic strategies. Our central hypothesis is that dysbiosis arising during HNSCC pathogenesis acts through Toll-like Receptor 2 signaling pathways to accelerate tumor development and compromise response to therapies directed at the PI3 kinase pathway, a key driver of HNSCC. This hypothesis has been formulated on the basis of publications and preliminary data produced in the applicants' laboratories and will be tested by pursuing two specific aims that will: 1) Test the hypothesis that TLR2 signaling mediates microbiome-related HNSCC pathogenesis and 2) Test the hypothesis that dysbiosis-stimulated TLR2 signaling compromises anti-PI3K therapy. Our approach is innovative because it represents a departure from the status quo by utilizing unique experimental mouse models and state-of-art technologies to move beyond observational human studies to delineate the molecular, cellular, and immunological mechanisms induced by the microbiome in HNSCC pathogenesis. The proposed research is significant because it is expected to advance and expand understanding of how the microbiome as a whole, as well as specific microbial species, impacts host immunity in HNSCC development and immunotherapy. Ultimately, such knowledge has the potential to be developed into effective therapies for HNSCC patients, a pressing need given the significant incidence and poor prognosis of this disease.

项目概要 尽管各方共同努力，头颈鳞状细胞癌（HNSCC）仍然是一种致命疾病 改善其诊断和治疗。尽管吸烟、饮酒和HPV感染密切相关 HNSCC，新出现的证据还表明，人类微生物组的变化与 HNSCC。然而，关于改变的微生物群如何影响 HNSCC 的发病机制或其相关机制，人们知之甚少。 治疗。目前，大多数将微生物群与癌症联系起来的研究都集中在肠道微生物群上， 要么局部促进结直肠癌发病机制，或更广泛地说，调节新陈代谢和 全身免疫力。口腔，与局部微环境关系更为直接。 HNSCC 是所有人体解剖学子部位中最复杂和最多样化的微生物组之一。 然而，肠道或口腔微生物群如何塑造 HNSCC 的局部和全身微环境 发病机制和治疗完全未知。 我们的长期目标是确定微生物组的功能作用和作用机制 HNSCC 并将这些发现转化为新的预防和治疗策略。我们的中央 假设 HNSCC 发病过程中出现的生态失调通过 Toll 样受体 2 信号传导起作用 加速肿瘤发展并损害针对 PI3 激酶的治疗反应的途径 途径，HNSCC 的关键驱动因素。该假设是根据出版物和文献提出的 申请人实验室产生的初步数据将通过追求两个具体目标进行测试： 将：1) 检验 TLR2 信号传导介导微生物组相关 HNSCC 发病机制的假设，以及 2) 检验生态失调刺激的 TLR2 信号传导损害抗 PI3K 治疗的假设。我们的方法是 创新，因为它通过利用独特的实验鼠标代表了对现状的背离 模型和最先进的技术超越观察性人类研究来描绘分子、 HNSCC 发病机制中微生物组诱导的细胞和免疫机制。拟议的 研究意义重大，因为它有望推进和扩大对微生物组如何发挥作用的理解 整个以及特定的微生物物种都会影响 HNSCC 发育和宿主免疫 免疫疗法。最终，这些知识有可能被开发成有效的治疗方法 鉴于该疾病的高发病率和不良预后，HNSCC 患者的迫切需求。