Impact of N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on the Progression of Melanoma

N-乙酰半乳糖胺-4-硫酸酯酶（芳基硫酸酯酶 B）对黑色素瘤进展的影响

• 批准号: 10399551
• 负责人: Joanne Kramer Tobacman
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10399551
• 关键词: Address; Affect; Apoptosis; Arylsulfatase B; Binding; Biological; Breast; CD34 gene; Cardiac; Cell Line; Cell Survival; Cell physiology; Cells; Characteristics; Chondroitin; Chondroitin Sulfate A; Chondroitin Sulfate Proteoglycan; Clinical; Coculture Techniques; Colon; Dermatan Sulfate; Disease; Doctor of Medicine; Doctor of Philosophy; Dose; Early Diagnosis; Effectiveness; Enzymes; Event; Excision; Family; Family member; Galectin 3; Gelatinase A; General Population; Genetic Transcription; Growth; Human; Immune; Immune checkpoint inhibitor; Immunooncology; Implant; Insulin Receptor; Investigation; Knockout Mice; Lead; Liver; Lymphocyte; Lysosomal Storage Diseases; MAP Kinase Gene; MAPK3 gene; MAPK8 gene; MMP2 gene; Malignant Neoplasms; Matrix Metalloproteinases; Measures; Mediator of activation protein; Melanoma Cell; Metastatic Melanoma; Modification; Morbidity - disease rate; Mucopolysaccharidosis VI; Mus; Mutation; Neurologic; Nuclear Translocation; Oncologist; Orthopedics; PTPN11 gene; Pathology; Patients; Phosphorylation; Prostate; Protein Dephosphorylation; Protein Tyrosine Phosphatase; Publications; Publishing; Radial; Recombinants; Recurrence; Reporting; Research Personnel; Role; Signal Transduction; Signaling Molecule; Stage at Diagnosis; Structure; Sulfatases; Sulfate; Testing; Time; Tissue Microarray; Tissues; Toxic effect; Transcription Coactivator; Treatment Effectiveness; Treatment Protocols; Veterans; Work; Xenograft Model; anti-PD1 therapy; base; cancer cell; checkpoint inhibition; checkpoint therapy; chondroitin sulfate glycosaminoglycan; enzyme activity; experience; experimental study; human tissue; humanized mouse; immunomodulatory therapies; insight; interest; knock-down; lead sulfate; melanocyte; melanoma; mortality; mouse model; novel; novel strategies; novel therapeutic intervention; overexpression; p38 Mitogen Activated Protein Kinase; pembrolizumab; polysulfated glycosaminoglycan; programmed cell death ligand 1; receptor binding; respiratory; response; transcription factor; transcriptome sequencing

The morbidity and mortality of malignant melanoma are significant problems for veterans, their families, and the general public. Progress has been made in early diagnosis and in treatment, in particular with advances in checkpoint inhibition therapy. However, not all patients respond to this approach and the treatment has major toxicity. There is a continuing unmet need for improvement in treatment of melanoma. This project presents a novel and potentially breakthrough treatment approach, based on the impact of the enzyme N- acetylgalactosamine-4-sulfatase, also known as arylsulfatase B (ARSB). This enzyme removes sulfate groups from chondroitin 4-sulfate (C4S) and dermatan sulfate and is required for the degradation of these sulfated glycosaminoglycans. Our previous work has shown that lower ARSB activity is associated with more aggressive melanomas. Also, decline in ARSB leads to increased expression of the melanoma proteoglycan chondroitin sulfate proteoglycan (CSPG)4 and of the matrix metalloproteinase pro-MMP2 which facilitates invasion. Other experiments have shown increase in PD-L1 expression in melanoma cells following ARSB silencing. In this project, we will determine the transcriptional mechanism by which decline in ARSB increases expression of PD-L1 in normal melanocytes and melanoma cells. Experiments will show how decline and increase in ARSB affect melanoma cell survival and intracellular signaling. The impact of anti-PD1 treatment on melanoma cell survival will be tested in live cell co-culture with immune cells following ARSB silencing. Other studies in the B16F10 and YUMM mouse models of melanoma and in a humanized mouse xenograft model will show the impact of modulation of ARSB in association with checkpoint inhibitor treatment on the progression of primary and metastatic melanomas. This project is based on over 30 publications in which Dr. Tobacman and collaborators have identified biological consequences of decline in ARSB. A previous report with project collaborator, Arkadiusz Dudek, M.D., Ph.D., a distinguished oncologist and investigator with strong interest, background, and clinical experience in immuno-oncology, identified decline in ARSB with increasing aggressiveness of melanoma cell lines, as well as significant increases in expression CSPG4 and pro-MMP2. Inborn deficiency of ARSB is present in the lysosomal storage disease Mucopolysaccharidosis (MPS) VI, in which mutations lead to marked reduction of ARSB activity. In malignant cells from prostate, breast, colon, and liver, as well as in melanoma cells and tissue, we have shown that expression and activity of ARSB are reduced, compared to normal melanocytes and tissue. Decline in ARSB leads to accumulation of the sulfated glycosaminoglycans chondroitin 4-sulfate and dermatan sulfate, from which ARSB normally removes the 4- sulfate group at the non-reducing end and is required to initiate their degradation. With decline in ARSB, C4S accumulates and its interactions with critical molecules are disrupted. We have shown that galectin-3, a co- transcriptional activator which binds to other important molecules, including the insulin receptor, binds less to more highly sulfated C4S and has increased nuclear translocation and interaction with transcription factors. Inversely, SHP2 (PTPN11), the ubiquitous non-membrane Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2, binds more with more highly sulfated C4S and is less available for dephosphorylation of critical signaling molecules, including phospho-ERK1/2. Hence, the transcriptional events arising from altered sulfation of C4S have profound impact on vital cellular processes. This project will provide new insight into how changes in ARSB, and the resulting changes in chondroitin 4-sulfation and signaling and transcriptional events, impact on melanoma progression and on response to checkpoint inhibition. The findings may lead to new approaches to treatment of melanoma and to improvement in response to checkpoint inhibition, resulting in reduced suffering, morbidity, and mortality from melanoma.

恶性黑色素瘤的发病率和死亡率是退伍军人及其家人面临的重大问题，