Microbial Dysbiosis in Pancreatic Cancer Initiation and Progression

胰腺癌发生和进展中的微生物失调

基本信息

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
项目类别：
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

项目摘要

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.

项目概要胰腺癌是一种毁灭性疾病，五年生存率仅为 10%。的崛起免疫疗法在许多癌症（如黑色素瘤）的治疗中取得了突破性进展，显着改善了病情生存结果。然而，与恶性黑色素瘤不同的是，我们看到生存率的变化很小胰腺癌，因为我们仍然不完全了解这种疾病中免疫的调节因素。细菌失调正在成为致癌的帮凶，并与胰腺癌有关癌症进展和较差的生存率。我们发现肠道细菌可以直接进入胰腺，并且胰腺肿瘤拥有独特的微生物群。肿瘤相关微生物组调节胰腺通过使肿瘤浸润免疫细胞偏向免疫抑制表型来控制癌症进展。然而，细菌调节免疫细胞功能的确切机制仍不清楚。肿瘤微环境中癌细胞和基质细胞的炎症信号传导已被证明极大地调节胰腺癌中的免疫细胞浸润。我们的初步数据表明病原菌可以直接与胰腺上皮细胞相互作用，诱导增殖和炎症反应。此外，我们发现肿瘤中细菌的存在会扭曲成纤维细胞向炎症、肿瘤促进表型分化。在本提案中，我们力求确定肿瘤相关细菌如何调节上皮细胞和基质细胞胰腺肿瘤微环境，从而帮助它们促进胰腺癌进展的能力。该应用程序的总体目标是支持我的持续培训和发展，成为一名微生物学和胰腺癌生物学的独立研究者。职业发展规划是基于正式的教学课程、体验式学习和指导的基础科学培训。我有得到了我所在部门的慷慨支持和受保护的时间，并将与我的导师密切合作 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。我也有建立了一个咨询委员会，拥有微生物学和细菌与宿主相互作用方面的专业知识，以进一步我在完成这个项目时接受了微生物学培训。我的研究兴趣的主要主题是该提案的具体目标体现在：（1）确定肿瘤相关细菌的影响对胰腺癌细胞 (2) 进行测定，以确定其激活和分化胰腺基质细胞的能力 (3) 进一步表征胰腺癌相关的独特致病机制细菌。成功完成这些拟议的实验将描绘出以下机制：微生物与肿瘤微环境中的非免疫细胞相互作用，并提供深入了解肠道微生物调节治疗胰腺癌的治疗策略。