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：
10670397
负责人：
Imayavaramban Lakshmanan
金额：
$ 20.93万
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/10670397
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 Chest 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 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 Tumor Promotion Xenograft procedure angiogenesis cancer cell cancer subtypes cell motility comparison control 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）是一种侵略性疾病，约占所有肺的85％癌症。尽管有最近的进步，但NSCLC患者的总体5年生存率仍然令人沮丧。肺腺癌（LUAD）是NSCLC最常见的亚型。 luad的高事件显示侵略性疾病，经常转移，预后不良。因此，了解 LUAD血管生成，肿瘤发育和转移的机制将显着改善LUAD 结果。 ST6GALNAC-I的独特表达以侵略性类型（KRASG12D/+; TRP53R172H/+; AD-鉴定 CRE（KPA））自围候肿瘤。 ST6GALNAC-I是一种O-糖基转移酶，它催化添加的添加唾液酸进入第一糖galnac（TN），并导致形成Neu5acα2，6galnac（stn）碳氢化物抗原。 ST6GALNAC-I KO细胞显示出LUAD细胞中脱酰缩粘的MUC5AC水平降低，ST6GALNAC- I KO或MUC5AC敲低（KD）细胞具有较小的血管生成和迁移潜力。特别是MUC5AC KD LC在两个肺中显示出明显降低器官特异性内皮结合和管的形成能力（HUVEC）和大脑（HBEC-5I）。基于这些研究，我们假设“ ST6GALNAC-I改变了MUC5AC LUAD肿瘤微环境中的糖基化并促进原发性肿瘤和通过整联蛋白β4的转移位点。为了检验这一假设，提出了两个特定的目的。目标1将全面定义ST6GALNAC-I对MUC5AC糖基化及其对肿瘤生长的影响和血管生成。 AIM 2将系统地描述ST6GALNAC-I介导的分子机制 MUC5AC糖基化及其在原发性和转移性部位的肿瘤微环境中的作用，特别是使用可用的鼠标模型的脑转移。为了证明这个概念，我们将使用st6galnac-i ko 或MUC5AC KO细胞系，经胸腔和心脏内转移模型以及MUC5AC敲除小鼠型号。我们还将使用3D器官模型研究MUC5AC表达肿瘤细胞和原发性和转移性位点中的非肿瘤细胞。它将突出显示的机械和功能意义细胞粘合剂和转移中的ST6GALNAC-I/MUC5AC轴。拟议的研究的主要影响将提供ST6GALNAC-I对MUC5AC溶解和该途径在肿瘤生长中的作用的影响和血管生成。该研究的结果将有助于设计新颖的疗法转移策略 luad患者。