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 癌症的标志特征之一是细胞糖基化的改变。本土化转型 癌症到转移性疾病通常会导致预后不良，其关键特征是专利的变化 糖基化。相比之下，转移性癌细胞合成异常水平和可变结构的聚糖 与非转移性对应物。转移相关聚糖可以改变细胞活性，例如 粘附、侵袭和增殖，以及促进促转移凝集素的结合。因此， 转移相关聚糖及其相关的聚糖合成酶为治疗提供了有吸引力的靶点 癌症进展的治疗干扰。根据这个合作UO1肿瘤糖组学 指令，我们寻求利用我们在细胞分析方面的互补专业知识和实验室进步 表面聚糖和肿瘤糖生物学，以检查聚糖结构的修饰如何影响 恶性进展。我们的指导假设是，获得不同的转移相关聚糖 影响恶性行为和转移潜力。在初步研究中，基因集富集分析 对 (9) 种常见人类癌症类型进行的研究表明，最重要的是，转移性黑色素瘤是 富含“糖组”基因特征。随后的糖组分析表明，转移性黑色素瘤 细胞独特地表现出高水平的i-线性聚-N-乙酰基乳糖胺（polylacs），而正常人 黑素细胞几乎只表达I-分支聚乳酸。进一步比较糖组基因谱 正常黑色素细胞和转移性黑色素瘤细胞之间发现 I 分支 ß1,6 水平受到抑制 转移性黑色素瘤细胞中的 N-乙酰氨基葡萄糖转移酶 (GCNT2) 与 黑色素瘤进展。在人类黑色素瘤模型中强制表达 GCNT2 强烈表明 I- Branch/GCNT2 导致体内黑色素瘤生长和细胞信号传导显着减弱 与胰岛素样生长因子-1 受体和 ß1 整合素相关的增殖。 I 分支 GCNT2 活性 还抑制促黑色素瘤转移凝集素、半乳糖凝集素 (Gal)-3 的结合。在这笔赠款中，我们将利用这些 令人兴奋的黑色素瘤糖组学数据研究 i-线性/I-分支聚乳酸和 GCNT2 作为调节剂的作用 转移性黑色素瘤行为。具体目标是：（1）分析I-支链聚糖的功能 和GCNT2对黑色素瘤细胞活性的影响以及（2）确定I-branch/GCNT2是否表达 预测黑色素瘤的进展。这些目标将由肿瘤专家协作团队探索 糖生物学、糖分析和黑色素瘤病理学，包括使用临床相关的人类和 小鼠黑色素瘤模型和创新的组织病理学、糖分析和基因调控系统。 我们的深远目标是了解黑色素瘤如何转移——黑色素瘤致死率的因果步骤 患者。重要的是，我们的研究结果将为糖组调节剂如何靶向治疗提供新的见解。 治疗开发或用作预测黑色素瘤转移和患者临床结果的生物标志物。