Spatially Resolved Metagenomics to Explore Tumor-Microbiome Interactions in Human Colorectal Cancer

空间分辨宏基因组学探索人类结直肠癌中肿瘤-微生物组的相互作用

• 批准号: 9795491
• 负责人: Ilana Lauren Brito
• 金额: $ 34.93万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9795491
• 关键词: Address; Affect; Architecture; Atlases; Automated Annotation; Bacteria; Bacteroides; Bioinformatics; Biopsy; Catalogs; Cells; Cessation of life; Colon Carcinoma; Colonic Adenoma; Colonic Neoplasms; Colorectal Cancer; Complex; Computer software; Consequentialism; Custom; DNA; DNA sequencing; Data; Development; Disease; Disease Progression; Distal; Epithelial; Epithelium; Event; Fluorescence Microscopy; Foundations; Fusobacterium nucleatum; Gene Expression; Genes; Genetic Transcription; Human; Image; Image Analysis; Imaging Techniques; Immune response; Inflammation; Investigation; Knowledge; Location; Malignant Neoplasms; Maps; Metagenomics; Methodology; Methods; Microbe; Microbial Biofilms; Microscope; Molecular Analysis; Molecular Biology; Mucous Membrane; Mucous body substance; Natural Killer Cells; Neoplasm Metastasis; Optics; Organism; Patients; Phylogenetic Analysis; Play; Prevotella; Procedures; RNA, Ribosomal, 16S; Resolution; Role; Selenomonas; Shotguns; Speed; Surface; Surveys; System; T-Lymphocyte; Technology; Testing; Time; Tissues; Validation; bacterial community; base; carcinogenesis; chemotherapy; colon microbiota; colorectal cancer progression; design; design and construction; dysbiosis; experimental study; flexibility; fluorophore; gut microbiome; host microbiome; hybrid gene; imaging software; improved; innovation; innovative technologies; instrument; microbial; microbial community; microbiome; microbiome research; microbiota; microorganism interaction; novel; quantitative imaging; rRNA Genes; response; spectrograph; tool; tumor; tumor growth; tumor initiation; tumor microbiome; tumor microenvironment; tumor progression; validation studies

PROJECT SUMMARY Microbes are increasingly recognized as a critical component of the tumor microenvironment of cancers that arise at epithelial barrier surfaces, such as human colorectal cancer (CRC). Spatial interactions between microbes and between microbes and host tissues, are fundamental to the mechanisms by which microbiota drive carcinogenesis in CRC, yet these interactions remain poorly studied. This lack of knowledge is in large part due to fundamental limitations of the tools available to study microbes and microbiomes. Microbiome studies primarily rely on shotgun DNA sequencing, which destroys all information about the spatial context of microbes and their functional interactions, or imaging methodologies that are limited to identifying a small number of organisms using general species marker tags. In this project, we will invent and apply spatially resolved metagenomics (SRM), a revolutionary molecular analysis technology that enables to create micro-scale maps of the locations of thousands of different bacterial species in dense microbial communities. SRM takes advantage of optical barcoding and spectral imaging-based barcode decoding, enabling the identification of bacterial species by their unique 16S ribosomal RNAs, and even quantification of host gene expression. SRM is a flexible and inexpensive technology that increases the number of unique microbial species that can be identified over existing methods by at least two orders of magnitude and is well supported by pilot data. We will investigate three aims. First, we will refine a host of innovative technologies that together lay the foundation for SRM, including but not limited to software for the automated design of hybridization probes, spectral imaging procedures and software for the automated annotation of images. Second, we will design and construct a custom broad-wavelength confocal microscope, that will improve the multiplexity, and speed of SRM by an additional order of magnitude, which in turn will improve the range of possible applications of SRM. Third, we will perform rigorous validation of SRM in experiments that address highly timely questions in human CRC. The functional roles of cancer-promoting microbes in CRC, the role for biofilm formation as a consequential, early event in CRC development, and the presence of a persistent microbiome in CRC tumors, are all very recent landmark discoveries, that we will be able to study with unprecedented spatial and phylogenetic resolution by taking advantage of the features SRM. SRM enables to survey not only who is there, but also who is next to who and who is next to what, and therefore provide a powerful, novel means to study the functional role of microbiota in the initiation and progression of CRC, a disease that accounts for more than 50,000 deaths annually in the US.

项目总结