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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.

项目总结