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Glycosylation as a Regulator of Tropism of Melanoma Metastasis - Resubmission - 1

糖基化作为黑色素瘤转移倾向的调节剂 - 重新提交 - 1

基本信息

批准号：
9822110
负责人：
Praveen Agrawal
金额：
$ 19.44万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9822110
关键词：
Affinity Chromatography Affinity Chromatography Area Area Asparagine Asparagine Bar Codes Biological Biological Biological Assay Biological Assay Biological Models Biological Models Biology Biology Brain Brain Cancer Biology Cancer Biology Cancer Patient Cancer Patient Carbohydrates Carbohydrates Cardiovascular system Cardiovascular system Cell Adhesion Cell Adhesion Cell Adhesion Molecules Cell Adhesion Molecules Cell surface Cell surface Cells Cells Cessation of life Cessation of life Clinical Clinical Complex Complex Coupling Coupling Disseminated Malignant Neoplasm Disseminated Malignant Neoplasm Distal Distal Distant Distant Enzymes Enzymes Epitopes Epitopes Fluorescence Fluorescence Fucosyltransferase Fucosyltransferase Genetic Transcription Genetic Transcription Glycoproteins Glycoproteins Glycoside Hydrolases Glycoside Hydrolases Homing Homing Immune Immune Immune Evasion Immune Evasion In Vitro In Vitro Invaded Invaded Investigation Investigation Knowledge Knowledge Laboratories Laboratories Lectin Lectin Libraries Libraries Link Link Liver Liver Lung Lung Lymphatic System Lymphatic System Malignant - descriptor Malignant - descriptor Malignant Neoplasms Malignant Neoplasms Malignant neoplasm of prostate Malignant neoplasm of prostate Mediating Mediating Melanoma Cell Melanoma Cell Metastatic Melanoma Metastatic Melanoma Metastatic malignant neoplasm to brain Metastatic malignant neoplasm to brain MicroRNAs MicroRNAs Movement Movement Mutate Mutate Neoplasm Metastasis Neoplasm Metastasis Neural Cell Adhesion Molecule L1 Neural Cell Adhesion Molecule L1 Non-Small-Cell Lung Carcinoma Non-Small-Cell Lung Carcinoma Organ Organ Pathway interactions Pathway interactions Patients Patients Pattern Pattern Pigments Pigments Polysaccharides Polysaccharides Primary Neoplasm Primary Neoplasm Process Process Prognosis Proliferating Proliferating Property Property Protein Glycosylation Protein Glycosylation Proteins Proteins Regulation Regulation Research Research Role Role Sampling Sampling Secondary to Secondary to Series Series Serine Serine Shotguns Shotguns Signal Pathway Signal Pathway Site Site Skin Skin Specificity Specificity Structure Structure Systems Biology Systems Biology Therapeutic Therapeutic Threonine Threonine Tissue Sample Tissue Sample Tissue Survival Tissue Survival Tropism Tropism Validation Validation Work Work Xenograft Model Xenograft Model angiogenesis angiogenesis bone bone cancer cell cancer cell cancer type cancer type candidate validation candidate validation capillary bed capillary bed cell motility cell motility clinically relevant clinically relevant data mining data mining differential expression differential expression glycoproteomics glycoproteomics glycosylation glycosylation glycosyltransferase glycosyltransferase high throughput screening high throughput screening in vitro Assay in vitro Assay in vitro Model in vitro Model in vivo in vivo in vivo Model in vivo Model innovation innovation insight insight liquid chromatography mass spectrometry liquid chromatography mass spectrometry lymph nodes lymph nodes malignant phenotype malignant phenotype melanocyte melanocyte melanoma melanoma metastatic process metastatic process mortality mortality neoplastic cell neoplastic cell novel therapeutics novel therapeutics outcome forecast programs programs screening screening small hairpin RNA small hairpin RNA treatment site treatment site tumor tumor tumor progression tumor progression

项目摘要

Glycosylation as a regulator of tropism of melanoma metastasis Malignant melanoma is a type of cancer arising from melanocytes, the pigmented cells of the skin. Metastases of tumors to secondary sites are the cause of 90% of cancer mortality. A salient feature of metastasis is the ability of a primary tumor to colonize secondary organs. This has prompted a quest to identify the factors and mechanisms that support melanoma metastasis to specific organs as secondary sites (e.g. brain, lung, liver). One of the most devastating complications of melanoma is that around 50% of patients with metastatic melanoma develop brain metastasis, after which most patients survive less than 6 months. Patients with brain metastasis don't benefit from new therapies and have extremely poor prognosis. Understanding the basis to brain and other organs adaptation may reveal new therapies. Carbohydrates, which are altered in tumors, are involved in immune evasion, homing of cells to tissues, survival, and anchorage. Our recent clinically relevant study identified distinct glycosylation patterns of primary and metastatic melanoma. Moreover, our preliminary studies of patient samples suggest that specific glycosylation patterns are a site- specific feature of metastasis. I hypothesize that adaptation of tumor cells to different secondary sites requires specific changes in cell surface glycosylation. My proposed work will use innovative approaches to identify therapeutically relevant glycan structures and glycosylation enzymes as targets for anti-metastatic therapies. I will identify candidate glycans and glycogenes to regulate site-specific metastasis through glycan profiling of relevant in vivo models and high-throughput screens with a barcoded pooled shRNA library of glycogenes. Candidate glycans and glycogenes will be validated by lectin fluorescence and IHC analysis of melanoma patient FFPE samples. We will further validate candidate glycogenes using in vivo xenograft models and dissect their mechanism of action through various in vitro assays. Further, we will use a glycoproteomic strategy, coupling lectin-affinity purification with LC/MS shotgun protein identification, to identify glycosylated proteins with a specific glycan motif. Finally, site-specific metastasis related glycoproteins would be investigated for their mechanism of action. The identification of glycans and glycosylation enzymes actively participating in melanoma tropism as well as a precise understanding of their mechanism of action has the potential to provide a trove of glycan epitopes and enzymes, that are unexplored as anti-tumor targets for the treatment of site-specific metastases.

糖基化对黑色素瘤转移倾向的调节作用