Shaping the Microenvironment by DPEP1 Facilitates Adenoma Progression

通过 DPEP1 塑造微环境促进腺瘤进展

• 批准号: 10518847
• 负责人: Robert J. Coffey
• 金额: $ 47.46万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518847
• 关键词: Attention; Behavior; Binding; Biological Assay; Biological Markers; Biological Process; Cell Line; Cells; Cellular biology; Characteristics; Coculture Techniques; Colon; Colonic Adenoma; Colorectal Adenoma; Colorectal Cancer; Communication; Confocal Microscopy; Data; Dipeptidases; Dipeptides; Electrical Resistance; Enzyme-Linked Immunosorbent Assay; Epithelial; Exposure to; Extracellular Matrix; Flow Cytometry; Future; Human; Immune; Immunofluorescence Immunologic; In Vitro; Knock-out; Knowledge; Lead; Lesion; Leukocyte Elastase; Malignant Neoplasms; Malignant neoplasm of pancreas; Manuscripts; Mediating; Monitor; Mus; Nature; Neoplasm Metastasis; Neutrophil Infiltration; Organoids; Patients; Polyps; Population; Property; Proteins; Reporter; Reporting; Role; Sampling; Selection Criteria; Shapes; Signal Transduction; Source; Specimen; Stains; System; Techniques; Testing; TimeLine; Tissue Microarray; Tissues; Tumor Suppressor Proteins; Western Blotting; adenoma; cancer biomarkers; cancer cell; colon cancer cell line; elastase inhibitor; exosome; extracellular vesicles; healthy volunteer; immunoreactivity; in vivo; interest; microbiota; mouse model; neutrophil; protein biomarkers; repository; single-cell RNA sequencing; spatial relationship; stem cells; transcriptome sequencing; tumor; tumor microenvironment; tumor progression

PROJECT SUMMARY/ABSTRACT Project 1: Shaping the Microenvironment by DPEP1 Facilitates Adenoma Progression Project 1 aims to examine how shaping the microenvironment by DPEP1 facilitates adenoma progression. This will be a basic project. We propose that dipeptidase-1 (DPEP1) marks those adenomas with the potential to progress to colorectal cancer (CRC) through an active bi-directional communication with neutrophils. DPEP1 has two functions: dipeptidase activity and recently identified neutrophil-binding activity. Our hypothesis is that DPEP1, largely through its neutrophil-binding activity, marks adenomas with a predilection for progression. We have found that DPEP1 immunoreactivity is detected in 27% of colorectal adenomas but this increases to 72% of CRCs, consistent with DPEP1 marking the small subset of adenomas that progress to CRC. Utilizing human specimens, a unique Transwell co-culture system of adenoma organoids and freshly isolated neutrophils isolated from healthy volunteers, and an informative mouse model, we will test if DPEP1-expressing adenomas more effectively communicate with neutrophils and create a neutrophil-enriched microenvironment, increasing the likelihood that these adenomas will progress. Exosomes have attracted a great deal of recent attention as a rich source of cargo that may serve as cancer biomarkers. We have found that DPEP1 is released in exosomes from CRC cell lines and that it highly enriched in a subset of exosomes that contain known CRC biomarkers, CEA and EPCAM. Of interest, neutrophils also release small extracellular vesicles (sEVs) that contain neutrophil elastase in a form that cannot be inhibited by elastase inhibitors, and thus it is especially potent in degrading the extracellular matrix, a key step in cancer invasion. We will also use a unique neutrophil reporter mouse to monitor onset and perdurance of neutrophil infiltration, along with the properties of these neutrophils, in an inducible, stem cell-driven mouse model of colonic adenomas. .

项目总结/文摘