Microbial Dysbiosis in Pancreatic Cancer Initiation and Progression

胰腺癌发生和进展中的微生物失调

• 批准号: 10723251
• 负责人: Donnele Daley
• 金额: $ 28.07万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723251
• 关键词: Ablation; Acceleration; Active Learning; Advisory Committees; Antibiotics; Area; Bacteria; Basic Science; Biological Assay; Biological Models; Cancer Biology; Cell Communication; Cell Proliferation; Cell physiology; Cells; Coculture Techniques; Combined Modality Therapy; Culture Techniques; Cytometry; Data; Development; Development Plans; Diagnosis; Disease; Doctor of Philosophy; Environment; Epithelial Cells; Epithelium; Event; Fibroblasts; Gastrointestinal tract structure; Gnotobiotic; Goals; Human; Hypoxia; Image; Immune; Immunity; Immunofluorescence Immunologic; Immunohistochemistry; Immunosuppression; Immunotherapy; In Vitro; Inflammatory; Inflammatory Response; Knock-out; Knowledge; Label; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Mentors; Metabolic; Microbe; Microbiology; Modeling; Mus; Organoids; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathogenicity; Pathologic; Patients; Phenotype; Production; Proliferating; Proteobacteria; Research; Research Personnel; Signal Transduction; Stromal Cells; System; TLR4 gene; Testing; Therapeutic; Time; Training; Transgenic Organisms; Tumor Promotion; Tumor-infiltrating immune cells; Up-Regulation; Work; advanced disease; cancer cell; cancer initiation; carcinogenesis; career development; cytokine; dysbiosis; experience; experimental study; gut bacteria; gut microbiome; immune cell infiltrate; improved; in vitro Model; in vivo; insight; interest; melanoma; member; microbial; microbiome; microbiome composition; mouse model; neoplastic cell; novel; pancreatic cancer cells; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pathogenic bacteria; recruit; screening; single-cell RNA sequencing; survival outcome; transcriptome sequencing; tumor; tumor growth; tumor microbiome; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

Project Summary Pancreatic adenocarcinoma is a devastating disease with a five-year survival of only 10%. The rise of immunotherapy has led to breakthrough treatments in many cancers, like melanoma, drastically improving survival outcomes. However, unlike malignant melanoma, we have seen minimal changes in survival for pancreatic cancer because we still do not completely understand the regulators of immunity in this disease. Bacterial dysbiosis is emerging as an accomplice to carcinogenesis and is associated with pancreatic cancer progression and poorer survival. We found that gut bacteria can directly access the pancreas, and pancreatic tumors harbor a unique microbiome. The tumor-associated microbiome regulates pancreatic cancer progression by skewing tumor-infiltrating immune cells towards an immunosuppressive phenotype. However, the exact mechanisms via which bacteria regulate immune cell function is still unknown. Inflammatory signaling in cancer cells and stromal cells in the tumor microenvironment has been shown to greatly regulate the immune cell infiltrate in pancreatic cancer. Our preliminary data suggests that pathogenic bacteria can directly interact with pancreatic epithelial cells inducing proliferation and an inflammatory response. Furthermore, we found that the presence of bacteria in tumors skews fibroblast differentiation towards an inflammatory, tumor-promoting phenotype. In this proposal, we seek to determine how tumor-associated bacteria modulate the epithelial and stromal compartments in the pancreatic tumor microenvironment thereby aiding their ability to promote pancreatic cancer progression. The overall goal of this application is to support my continued training and development to become an independent investigator in microbiology and pancreas cancer biology. The career development plan is based on formal didactic coursework, experiential learning, and mentored basic science training. I have received generous support and protected time from my department and will work closely with my mentor Dr. Marina Pasca di Magliano, PhD a respected and experienced pancreatic cancer biologist. I have also constructed an advisory committee, with expertise in microbiology and bacteria-host interaction to further my microbiology training while completing this project. The major themes of my research interests are reflected in the Specific Aims of this proposal: (1) to determine the influence of tumor-associated bacteria on pancreatic cancer cells (2) to determine their ability to activate and differentiate pancreatic stromal cells and (3) to further characterize the mechanisms of pathogenicity unique to pancreatic cancer-associated bacteria. Successful completion of these proposed experiments will delineate the mechanisms via which microbes interface with non-immune cells in the tumor microenvironment, and provide insight into therapeutic strategies for gut microbial modulation in treating pancreatic cancer.

项目摘要 胰腺癌是一种毁灭性的疾病，五年生存率仅为10%。的崛起 免疫疗法已经导致了许多癌症的突破性治疗，如黑色素瘤， 生存结果。然而，与恶性黑色素瘤不同的是，我们已经看到， 胰腺癌，因为我们仍然不完全了解这种疾病的免疫调节。 细菌生态失调正在成为致癌的帮凶，并与胰腺癌的发生有关。 癌症进展和较差的存活率。我们发现肠道细菌可以直接进入胰腺， 胰腺肿瘤具有独特的微生物组。肿瘤相关微生物组调节胰腺癌 通过使肿瘤浸润性免疫细胞偏向免疫抑制表型来抑制癌症进展。 然而，细菌调节免疫细胞功能的确切机制仍然未知。 肿瘤微环境中的癌细胞和基质细胞中的炎症信号传导已被证明是 对胰腺癌的免疫细胞浸润有很大的调节作用。我们的初步数据显示， 致病菌可以直接与胰腺上皮细胞相互作用，诱导增殖， 炎症反应。此外，我们发现肿瘤中细菌的存在使成纤维细胞 向炎性肿瘤促进表型分化。在本建议中，我们力求 确定肿瘤相关细菌如何调节上皮和基质区室， 胰腺肿瘤微环境，从而帮助其促进胰腺癌进展的能力。 这个应用程序的总体目标是支持我继续培训和发展，成为一个 微生物学和胰腺癌生物学独立研究员。职业发展计划是 基于正式的教学课程，体验式学习，并指导基础科学培训。我有 我从我的部门得到了慷慨的支持和保护时间，并将与我的导师密切合作 博士Marina Pasca di Magliano博士是一位受人尊敬且经验丰富的胰腺癌生物学家。我也 建立了一个咨询委员会，具有微生物学和细菌-宿主相互作用方面的专门知识， 完成这个项目的同时我还在接受微生物学培训我的研究兴趣的主要主题是 本建议的具体目的体现在：（1）确定肿瘤相关细菌的影响 胰腺癌细胞（2），以确定其激活和分化胰腺基质细胞的能力 和（3）进一步表征胰腺癌相关的独特的致病机制， 细菌成功完成这些拟议的实验将描绘的机制， 微生物与肿瘤微环境中的非免疫细胞相互作用， 用于治疗胰腺癌的肠道微生物调节的治疗策略。