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Project 2: Cellular topography and function of the breast cancer tissue microenvironment

项目2：乳腺癌组织微环境的细胞形态和功能

基本信息

批准号：
10272390
负责人：
Robert michael Angelo
金额：
$ 26.33万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-14 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10272390
关键词：
2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Antibodies Archives Automobile Driving Avidity Biopsy Breast cancer metastasis CRISPR interference Cell Communication Cells Clinical Collagen Data Data Set Deaminase Disease Progression Distant Enzymes Estrogen receptor positive Excision Extracellular Matrix Family Fibroblasts Frequencies Hydroxylation Image Immune Immune Evasion Immunosuppression Label Libraries Location Machine Learning Maps Mass Spectrum Analysis Metabolic Metals Metastatic breast cancer Metastatic to Methods Mixed Function Oxygenases Modeling Modification Molecular Morphology Multiplexed Ion Beam Imaging Neighborhoods Neoplasm Metastasis Nivolumab Normal tissue morphology Operative Surgical Procedures Organoids Outcome Pathogenesis Patients Peptide Hydrolases Peptides Play Polysaccharides Population Process Procollagen-Proline Dioxygenase Protein Glycosylation Proteins Proteomics Resolution Resources Risk Role Sampling Site Specimen Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Stains Stromal Cells Structural Protein Structure Testing Therapeutic Time Tissue Sample Tissue imaging Tissues Tumor Cell Migration Work biobank breast cancer progression breast imaging cell type clinically significant collagenase crosslink glycosylation glycosyltransferase high risk imaging modality immune activation macrophage malignant breast neoplasm neoplastic cell prevent receptor recruit response tool transcriptomics triple-negative invasive breast carcinoma tumor tumor microenvironment

项目摘要

Abstract/Project Summary Breast cancer (BC) metastasis is an emergent feature that occurs when the tumor’s ability to recruit metabolic resources, avoid immune activation, and disseminate to distant sites exceeds the capacity of surrounding normal tissue to prevent these processes. In line with this, work over the last decade has demonstrated the crucial role played by the tumor microenvironment (TME) in promoting or deterring BC progression. Tumor cell migration and immune recruitment have both been shown to be heavily influenced by fibroblasts and the surrounding extracellular matrix (ECM) they produce. Additionally, protein glycosylation has been shown to modulate these interactions. To understand how tumor glycosylation and ECM remodeling interact to potentiate BC metastasis, we will use spatial transcriptomics and two complementary mass spectrometry methods, MIBI-TOF and MALDI, to identify glycan-dependent, cell-cell, and cell-ECM interactions that shift the TME toward tumor permissive states. All three analyses will be performed on spatially-coregistered serial sections from the same tissue blocks. In doing so, comprehensive single-cell maps of each tissue sample constructed by MIBI-TOF can be directly superimposed with de novo proteomic and transcriptomic data. We will map and enumerate the lineage and major functional subsets of tumor and stromal cells with respect to relevant therapeutic and molecular parameters to understand how the BC TME evolves with disease progression. These features will be overlaid with de novo imaging of tissue glycans to identify potential mechanisms of immune evasion that involve tumor sialoglycans and macrophage-bound SIGLECs. The frequency and spatial enrichment of these features will be correlated with spatial transcriptomics data to identify regulatory glycosyltransferases promoting these interactions. Next, ECM-MALDI and MIBI-TOF data will be used to identify how collagen type, hydroxylation, and crosslinking shift in coordination with the collagen structure and function of neighboring cell populations. In particular, we will focus on understanding how the activity of two families of enzymes, prolyl and lysyl hydroxylases, drive structural changes in the ECM that promote BC metastasis. The clinical significance of these extracted cellular and molecular definitions of ECM remodeling will be assessed with respect to metastatic risk, stage, and IC subtype. Taken together, this work will provide an unprecedented view into how TME structure and cell-cell interactions between tumor and stroma relate to specific facets of the tumor ECM and glycome.

抽象/项目总结