Functional Analysis of Galectin-1 Ligands in Melanoma Progression

Galectin-1 配体在黑色素瘤进展中的功能分析

• 批准号: 9265414
• 负责人: CHARLES J DIMITROFF
• 金额: $ 36.16万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-02 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265414
• 关键词: Address; Adhesions; Apoptosis; Australia; Behavior; Benign; Binding; CD146 antigen; Carbohydrates; Cell Adhesion; Cell surface; Chimera organism; Clinical; Compound Nevus; Data; Development; Disease Progression; Dysplastic Nevus; Engineering; Epitopes; Event; Galactosides; Galectin 1; Glycobiology; Glycoproteins; Goals; Grant; Histology; Histopathology; Human; Immunity; Institutes; Investigation; Laboratories; Lectin; Ligand Binding; Ligands; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator of activation protein; Melanoma Cell; Membrane Glycoproteins; Membrane Proteins; Metastatic Melanoma; Molecular; Neoplasm Metastasis; Nevus; Outcome; Pathologist; Pathology; Patients; Polysaccharides; Proteins; Regulation; Research; Research Project Grants; Scaffolding Protein; Severity of illness; Sialyltransferases; Skin; Specimen; Structural Biochemistry; Structure; Surface; T-Lymphocyte; TNFSF11 gene; Tissues; Tumorigenicity; angiogenesis; cancer cell; cell motility; cohort; cytokine; differential expression; follow-up; glycoproteomics; glycosyltransferase; insight; melanocyte; melanoma; melanoma biomarkers; migration; neoplastic; neoplastic cell; novel; overexpression; sugar; tool; tumor; tumorigenic

DESCRIPTION (provided by applicant): Cell surface carbohydrates and proteins (lectins) that bind them are conspicuously elevated in certain malignancies. These sugar structures and lectins are critically involved in cancer cell motility, invasion and/or migration that ultimately evoke the lethality of cancer. There is a convincing body of evidence suggesting that ß-galactoside-binding lectin, galectin-1 (Gal-1), is a major glycopathogenic mediator of melanoma progression and metastasis. Studies show that melanoma-derived Gal-1 has a major impact on T cell-mediated anti-melanoma immunity. While most have focused on Gal-1 and its functional activity in these malignancy-related events, few have focused on the functional expression of Gal-1 carbohydrate-binding determinants found on the surface of melanoma cells. We have exciting preliminary data showing that human melanoma cells express a robust level of Gal-1-binding carbohydrates, including the membrane protein(s) that display them, that, to our surprise, are conspicuously absent on normal melanocytes and benign melanocytes in mildly dysplastic nevi. Moreover, we have experimental evidence indicating that melanoma cell adhesion molecule (MCAM) is the principal membrane glycoprotein displaying these Gal-1-binding carbohydrates that is also upregulated in malignant melanoma. Differential expression of these Gal-1-binding carbohydrates on distinct glycoproteins, operationally referred to as Gal-1 ligands, could, therefore, functionally correlate with malignant progression of human melanoma. Our central hypothesis is that expression of Gal-1 ligands, namely MCAM, on melanoma cells can not only be used as a biomarker of melanoma progression, but can be functionally associated with malignant transformation. The overall objective of this research project is to analyze the identity, regulation and function of Gal-1 ligands on human malignant melanoma cells and to study the utility of Gal-1 ligands as predictors of human melanoma progression and metastasis. Investigating identity and function of Gal-1 ligands in human melanomas and whether these structures correlate with disease severity and long-term outcome in melanoma patients can be uniquely applied by the tumor biologists and dermato-pathologists collaborating in this proposal. Using new Gal-1 ligand-binding probes developed by our laboratory and our collective expertise in identifying lectin ligands and studying the histopathology of melanomas, the Specific Aims are as follows: (1) To identify and characterize Gal-1 ligands in human melanomas and (2) To study the expression of Gal-1 ligands as predictors of melanoma progression. These studies will implement a unique cohort of human melanoma tissues from the Melanoma Institute of Australia to help determine whether Gal-1 ligand expression correlates with melanoma progression and metastasis. Moreover, we will employ state-of-the-art glycobiological tools to help dissect Gal-1 ligand identity and function. Importantly, our findings will provide novel molecular insights into the glyco-histopathology of melanomas, while offering new glycomic targets for predicting malignancy and/or clinical outcome.

描述(申请人提供)：细胞表面碳水化合物和结合它们的蛋白质(凝集素)在某些恶性肿瘤中明显升高。这些糖结构和凝集素与癌细胞的运动、侵袭和/或迁移密切相关，最终导致癌症的致命性。有大量令人信服的证据表明，半乳糖苷结合凝集素Galectin-1(Galectin-1)是黑色素瘤进展和转移的主要糖病理调节因子。研究表明，黑色素瘤来源的Gal-1对T细胞介导的抗黑色素瘤免疫有重要影响。虽然大多数人关注Gal-1及其在这些恶性肿瘤相关事件中的功能活性，但很少有人关注黑色素瘤细胞表面发现的Gal-1碳水化合物结合决定因素的功能表达。我们有令人兴奋的初步数据显示，人类黑色素瘤细胞表达强健水平的Gal1结合碳水化合物，包括显示它们的膜蛋白(S)，令我们惊讶的是，正常黑素细胞和轻度发育不良痣的良性黑素细胞明显缺乏这种碳水化合物。此外，我们有实验证据表明，黑色素瘤细胞黏附分子(MCAM)是显示这些Gal-1结合碳水化合物的主要膜糖蛋白，这种糖蛋白在恶性黑色素瘤中也上调。因此，这些与Gal-1结合的碳水化合物在不同的糖蛋白上的差异表达可能与人类黑色素瘤的恶性进展有关。我们的中心假设是，在黑色素瘤细胞上表达Gal-1配体，即MCAM，不仅可以作为黑色素瘤进展的生物标志物，而且可以在功能上与恶性转化相关。本研究的总体目标是分析Gal-1配体对人恶性黑色素瘤细胞的识别、调控和功能，并研究Gal-1配体作为预测人类黑色素瘤进展和转移的作用。研究人类黑色素瘤中Gal-1配体的身份和功能，以及这些结构是否与黑色素瘤患者的疾病严重程度和长期结果相关，可以由参与这一提议的肿瘤生物学家和皮肤病理学家独一无二地应用。利用我们实验室开发的新的Gal-1配体结合探针和我们在鉴定凝集素配体和研究黑色素瘤组织病理学方面的集体专业知识，具体目的如下：(1)鉴定和表征人类黑色素瘤中的Gal-1配体；(2)研究Gal-1配体的表达作为黑色素瘤进展的预测因素。这些研究将实施来自澳大利亚黑色素瘤研究所的一组独特的人类黑色素瘤组织，以帮助确定Gal-1配体的表达是否与黑色素瘤的进展和转移相关。此外，我们将使用最先进的糖生物学工具来帮助剖析Gal-1配体的身份和功能。重要的是，我们的发现将为黑色素瘤的糖组织病理学提供新的分子见解，同时为预测恶性和/或临床结果提供新的血糖靶点。

项目成果

Galectin-9 suppresses B cell receptor signaling and is regulated by I-branching of N-glycans.

• DOI: 10.1038/s41467-018-05770-9
• 发表时间: 2018-08-17
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Giovannone N;Liang J;Antonopoulos A;Geddes Sweeney J;King SL;Pochebit SM;Bhattacharyya N;Lee GS;Dell A;Widlund HR;Haslam SM;Dimitroff CJ
• 通讯作者: Dimitroff CJ

Adenosine A(2A) receptor up-regulates retinal wave frequency via starburst amacrine cells in the developing rat retina.

• DOI: 10.1371/journal.pone.0095090
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Huang PC;Hsiao YT;Kao SY;Chen CF;Chen YC;Chiang CW;Lee CF;Lu JC;Chern Y;Wang CT
• 通讯作者: Wang CT

Galectin-Binding O-Glycosylations as Regulators of Malignancy.

• DOI: 10.1158/0008-5472.can-15-0834
• 发表时间: 2015-08-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Dimitroff CJ