Analysis of Glycomic Regulators in Melanoma Progression

黑色素瘤进展中的糖调节因子分析

• 批准号: 10414886
• 负责人: CHARLES J DIMITROFF
• 金额: $ 47.68万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414886
• 关键词: Adhesions; Archives; Behavior; Binding; Biological Markers; Cancer Model; Cell Proliferation; Cell surface; Cells; Clinical; Complement; Data; Disease; Disease Marker; Disease Progression; Disseminated Malignant Neoplasm; Enzymes; Galactose; Galectin 3; Gene Expression; Gene Expression Regulation; Gene set enrichment analysis; Genes; Glycobiology; Goals; Grant; Growth; Growth Factor; Human; IGF1R gene; Insulin; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Integrins; Knowledge; Laboratories; Lectin; Legal patent; Ligands; Link; Localized Malignant Neoplasm; Malignant - descriptor; Malignant Neoplasms; Melanoma Cell; Metastatic Melanoma; Metastatic to; Methods; Modeling; Modification; Mus; N-Acetylglucosaminyltransferases; N-acetyllactosamine; Neoplasm Metastasis; Nonmetastatic; Outcome; Pathology; Patient-Focused Outcomes; Patients; Polysaccharides; Prognosis; Regulation; Role; Signal Transduction; Specimen; Structure; Surface; System; Therapeutic; Virulent; Xenograft Model; anti-cancer; attenuation; cancer cell; cancer type; clinically relevant; comparative; experimental study; genetic signature; glycosylation; glycosyltransferase; in vivo; innovation; insight; melanocyte; melanoma; novel; receptor; targeted treatment; tumor; tumor progression

PROJECT ABSTRACT One of the hallmark features of cancer is the alteration of cellular glycosylation. The transition of localized cancer to metastatic disease, which commonly leads to poor prognosis, critically features patent changes in glycosylation. Metastatic cancer cells synthesize aberrant levels and variable structures of glycans compared with their non-metastatic counterparts. Metastasis-associated glycans can modify cellular activities, such as adhesion, invasion and proliferation, as well as encourage binding of pro-metastatic lectins. Hence, metastasis-associated glycans and their related glycan-synthesizing enzymes offer attractive targets for therapeutic interference of cancer progression. In accordance with this collaborative UO1 tumor glycomics directive, we seek to leverage our complementary expertise and laboratory advances on analytics of cell surface glycans and on tumor glycobiology to examine how modifications in glycan structure influence malignant progression. Our guiding hypothesis is that acquisition of distinct metastasis-associated glycans impacts malignant behavior and metastatic potential. In preliminary studies, gene set enrichment analysis performed across (9) common human cancer types indicated that metastatic melanomas, above all, were enriched for a `glycome' gene signature. Subsequent glycomic analysis indicated that metastatic melanoma cells uniquely displayed a high level of i-linear poly-N-acetyllactosamines (polylacs), whereas normal human melanocytes almost exclusively expressed I-branched polylacs. Further comparative glycome gene profiling between normal melanocytes and metastatic melanoma cells identified suppressed levels of I-branching ß1,6 N-acetylglucosaminyltransferase (GCNT2) in metastatic melanoma cells that was significantly correlated with melanoma progression. Enforced GCNT2 expression in human melanoma models strongly indicated that I- branch/GCNT2 caused significant attenuation of melanoma growth in vivo and of cell signaling and proliferation associated with insulin-like growth factor-1 receptor and ß1 integrins. I-branching GCNT2 activity also inhibited binding of pro-melanoma metastasis lectin, galectin (Gal)-3. In this grant, we will leverage these exciting melanoma glycomic data to investigate the role of i-linear/I-branch polylacs and GCNT2 as regulators of metastatic melanoma behavior. The Specific Aims are: (1) To analyze function of I-branched glycans and GCNT2 on melanoma cell activity and (2) To determine whether I-branch/GCNT2 expression predicts melanoma progression. These Aims will be explored by a collaborative team of experts in tumor glycobiology, glyco-analytics and melanoma pathology and include the use of clinically-relevant human and mouse melanoma models and innovative histo-pathological, glyco-analytical and gene regulation systems. Our far-reaching goal is to understand how melanomas metastasize - the causal step of melanoma lethality in patients. Importantly, our findings will offer new insights into how glycomic regulators can be targeted for therapeutic exploitation or used as biomarkers to predict melanoma metastasis and clinical outcome in patients.

项目摘要 癌症的标志性特征之一是细胞糖基化的改变。本地化的过渡 转移性疾病的癌症通常导致预后不良，批判性的特征是专利变化 糖基化。转移性癌细胞合成异常水平和聚糖的可变结构 与他们的非转移性对应物。转移相关的聚糖可以改变细胞活性，例如 粘附，入侵和增殖，以及促旋转式讲座的鼓励结合。因此， 转移相关的聚糖及其相关的聚糖合成酶为 癌症进展的治疗干扰。根据此协作的UO1肿瘤糖胶质 指令，我们试图利用我们的完善专业知识和实验室的细胞分析进步 表面聚糖和肿瘤糖生物学，以检查聚糖结构中的修饰如何影响 恶性进展。我们的指导假设是获得不同转移相关的聚糖 影响恶性行为和转移潜力。在初步研究中，基因集富集分析 在（9）常见的人类癌类型中进行的表明转移性黑色素瘤最重要的是 富含“糖”基因签名。随后的糖菌分析表明转移性黑色素瘤 细胞独特地显示了高水平的I线性聚-N-乙酰氨基甲胺（polylacs），而正常人 黑素细胞几乎完全表达了I支柱的polylacs。进一步的比较Glyce基因分析 在正常的黑素细胞和转移性黑色素瘤细胞之间鉴定出抑制水平的I-分支ß1,6 转移性黑色素瘤细胞中的N-乙酰基葡萄氨酰转移酶（GCNT2），与与与 黑色素瘤进展。在人黑色素瘤模型中强迫GCNT2表达强烈表明I- 分支/GCNT2在体内和细胞信号传导和 与胰岛素样生长因子-1受体和β1整合素相关的增殖。 I分支GCNT2活动 还抑制了前甲状腺瘤转移讲座的结合，半乳糖素（GAL）-3。在这笔赠款中，我们将利用这些 令人兴奋的黑色素瘤糖胶数据研究I线性/I分支小polyc和GCNT2作为调节剂的作用 转移性黑色素瘤行为。具体目的是：（1）分析i支线聚糖的功能 和GCNT2在黑色素瘤细胞活性上，以及（2）确定I-Branch/GCNT2表达是否表达 预测黑色素瘤进展。这些目标将由肿瘤专家的协作团队探索 糖生物学，糖 - 分析学和黑色素瘤病理学，包括使用与临床相关的人类和 小鼠黑色素瘤模型和创新的组织病理学，糖 - 分析和基因调节系统。 我们深远的目标是了解黑色素瘤如何转移 - 黑色素瘤致死性的一步 患者。重要的是，我们的发现将提供有关如何将糖浆调节剂作为目标的新见解 治疗性剥削或用作生物标志物预测患者的黑色素瘤转移和临床结果。