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：
10704687
负责人：
Robert michael Angelo
金额：
$ 34.15万
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/10704687
关键词：
2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Antibodies Automobile Driving Avidity Binding 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 Invaded Label Libraries Location Machine Learning Macrophage Maps Mass Spectrum Analysis Metabolic Metals Metastatic breast cancer 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 Structure Testing Therapeutic Time Tissue Sample Tissue imaging Tissues Tumor Cell Migration Visualization Work biobank breast cancer progression breast imaging cell type clinically significant collagenase crosslink glycosylation glycosyltransferase high risk imaging modality immune activation malignant breast neoplasm mass spectrometric imaging neoplastic cell permissiveness prevent receptor recruit response sialylation 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.

摘要/项目摘要乳腺癌 (BC) 转移是一种新兴特征，当肿瘤招募代谢能力时就会出现这种情况。资源，避免免疫激活，并传播到超出周围正常能力的远距离站点与此相一致的是，过去十年的工作已经证明了组织的关键作用。肿瘤微环境 (TME) 在促进或阻止肿瘤细胞迁移方面发挥着重要作用。和免疫招募都被证明受到成纤维细胞和周围环境的严重影响它们产生的细胞外基质（ECM）此外，蛋白质糖基化已被证明可以调节这些。了解肿瘤糖基化和 ECM 重塑如何相互作用以增强 BC 转移，我们将使用空间转录组学和两种互补的质谱方法，MIBI-TOF 和 MALDI，识别聚糖依赖性、细胞-细胞和细胞-ECM 相互作用，使 TME 向肿瘤许可方向转变所有三种分析都将在来自相同组织块的空间配准连续切片上进行。这样，通过 MIBI-TOF 构建的每个组织样本的综合单细胞图谱可以直接与从头蛋白质组学和转录组学数据叠加，我们将绘制谱系并进行计数。肿瘤和基质细胞在相关治疗和分子方面的主要功能亚群参数以了解 BC TME 如何随疾病进展而变化。这些特征将被叠加。通过组织聚糖的从头成像来识别涉及肿瘤的免疫逃避的潜在机制这些特征的频率和空间富集将是唾液酸聚糖和巨噬细胞结合的 SIGLEC。与空间转录组数据相关，以确定促进这些的调节性糖基转移酶接下来，ECM-MALDI 和 MIBI-TOF 数据将用于确定胶原蛋白类型、羟基化和相互作用。交联转变与邻近细胞群的胶原结构和功能协调。特别是，我们将重点了解两个酶家族（脯氨酰和赖氨酰）的活性如何羟化酶，驱动 ECM 的结构变化，促进 BC 转移。提取的 ECM 重塑的细胞和分子定义将根据转移风险进行评估，总而言之，这项工作将为 TME 的结构提供前所未有的视角。肿瘤和基质之间的细胞间相互作用与肿瘤 ECM 和糖组的特定方面有关。