ST6GalNAc-I/MUC5AC promoting angiogenesis in lung adenocarcinoma

ST6GalNAc-I/MUC5AC促进肺腺癌血管生成

基本信息

批准号：
10513140
负责人：
Imayavaramban Lakshmanan
金额：
$ 17.77万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10513140
关键词：
3-Dimensional A549 Accounting Address Adenocarcinoma Cell Adhesions Affinity Antigens Astrocytes Binding Biological Assay Biology Brain Brain Neoplasms Cancer Patient Carbohydrates Cell Adhesion Cell Line Cell physiology Cells Chemotaxis Development Disease Endothelial Cells Endothelium Focal Adhesion Kinase 1 Genes Genetically Engineered Mouse Growth Incidence Integrin beta4 KRASG12D Knock-out Knockout Mice Lung Lung Adenocarcinoma Lung Neoplasms MUC5AC gene Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Mediating Metastatic malignant neoplasm to brain Migration Assay Modeling Molecular Molecular Profiling Mucins Mus Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Organ Organoids Outcome Outcome Study PDE3A gene product Pathogenesis Pathway interactions Patients Play Polysaccharides Primary Neoplasm Process Prognosis Property Role Sialic Acids Signal Transduction Site Survival Rate Testing Tissues Tube Tumor Angiogenesis Xenograft procedure angiogenesis base cancer cell cancer subtypes cell motility conditional knockout design experimental study glycoproteomics glycosylation glycosyltransferase improved improved outcome knock-down migration molecular marker mouse model neoplastic cell new therapeutic target novel therapeutic intervention novel therapeutics overexpression prevent sialylation sugar therapeutic target three dimensional cell culture transcriptome transcriptomics tumor tumor growth tumor microenvironment tumor progression

项目摘要

Abstract Non-small cell lung cancer (NSCLC) is an aggressive disease accounting for approximately 85% of all lung cancers. Despite recent advances, the overall 5-year survival rate remains dismal for NSCLC patients. Lung adenocarcinoma (LUAD) is the most common subtype of NSCLC. A high incidence of LUAD displays an aggressive disease, frequent metastasis and is associated with poor prognosis. Hence, understanding the mechanisms behind LUAD angiogenesis, tumor development, and metastasis would significantly improve LUAD outcomes. The unique expression of St6galnac-I was identified in aggressive type (KrasG12D/+; Trp53R172H/+; Ad- Cre (KPA)) autochthonous tumors. ST6GalNAc-I is an O-glycosyltransferase, which catalyzes the addition of sialic acid onto first sugar GalNAc (Tn) and results in the formation of Neu5Acα2, 6GalNAc (STn) carbohydrate antigen. ST6GalNAc-I KO cells showed a reduced level of sialylated MUC5AC in LUAD cells, and ST6GalNAc- I KO or MUC5AC knockdown (KD) cells had less angiogenesis and migratory potential. In particular, MUC5AC KD LC showed significantly reduced organ-specific endothelial binding and tube formation ability in both lung (HUVEC) and brain (HBEC-5i). Based on these studies, we hypothesize that “ST6GalNAc-I alters MUC5AC glycosylation in the LUAD tumor microenvironment and promotes angiogenesis in both the primary tumor and metastatic sites through integrin β4.” To test this hypothesis, two specific aims are proposed. Aim 1 will comprehensively define the impact of ST6GalNAc-I on MUC5AC glycosylation and its impact on tumor growth and angiogenesis. Aim 2 will systemically delineate the molecular mechanism of ST6GalNAc-I mediated MUC5AC glycosylation and their role in the tumor microenvironment in both primary and metastatic sites, especially brain metastasis, using available mouse models. To prove this concept, we will use ST6GalNAc-I KO or MUC5AC KO cell lines, transthoracic and intracardiac metastatic models, and Muc5ac knockout mouse models. We will also use 3D organoid models to study the interaction of MUC5AC expressing tumor cells and non-tumor cells in primary and metastatic sites. It will highlight the mechanistic and functional significance of the ST6GalNAc-I/MUC5AC axis in cellular adhesion and metastasis. The major impact of the proposed study would be to provide the impact of ST6GalNAc-I on MUC5AC sialylation and the role of this pathway in tumor growth and angiogenesis. The outcomes from the study will help to design novel therapeutic strategies for metastatic LUAD patients.

抽象的非小细胞肺癌 (NSCLC) 是一种侵袭性疾病，约占所有肺癌的 85% 尽管最近取得了进展，但非小细胞肺癌患者的总体 5 年生存率仍然很低。腺癌 (LUAD) 是 NSCLC 最常见的亚型，LUAD 的高发病率表明侵袭性疾病、频繁转移并与不良预后相关。 LUAD 血管生成、肿瘤发展和转移背后的机制将显着改善 LUAD 结果 St6galnac-I 的独特表达在侵袭型中被鉴定（KrasG12D/+；Trp53R172H/+；Ad-）。 Cre (KPA)) 本土肿瘤 ST6GalNAc-I 是一种 O-糖基转移酶，可催化添加唾液酸结合到第一个糖 GalNAc (Tn) 上并导致形成 Neu5Acα2、6GalNAc (STn) 碳水化合物 ST6GalNAc-I KO细胞显示LUAD细胞中唾液酸化MUC5AC水平降低，并且ST6GalNAc- I KO或MUC5AC敲低（KD）细胞具有较少的血管生成和迁移潜力，特别是MUC5AC。 KD LC 显示双肺器官特异性内皮结合和管形成能力显着降低 (HUVEC) 和大脑 (HBEC-5i) 基于这些研究，我们认为“ST6GalNAc-I 改变了 MUC5AC”。 LUAD 肿瘤微环境中的糖基化并促进原发肿瘤和为了检验这一假设，我们提出了两个具体目标。全面定义ST6GalNAc-I对MUC5AC糖基化的影响及其对肿瘤生长的影响目标 2 将系统地描述 ST6GalNAc-I 介导的分子机制。 MUC5AC糖基化及其在原发和转移部位肿瘤微环境中的作用，特别是脑转移，使用现有的小鼠模型来证明这个概念，我们将使用 ST6GalNAc-I KO。或MUC5AC KO细胞系、经胸和心内转移模型以及Muc5ac敲除小鼠我们还将使用 3D 类器官模型来研究表达 MUC5AC 的肿瘤细胞与肿瘤细胞之间的相互作用。它将强调原发和转移部位的非肿瘤细胞的机制和功能意义。 ST6GalNAc-I/MUC5AC 轴在细胞粘附和转移中的主要影响将是该研究的主要影响。提供 ST6GalNAc-I 对 MUC5AC 唾液酸化的影响以及该途径在肿瘤生长中的作用该研究的结果将有助于设计新的转移性治疗策略。 LUAD 患者。