Targeting ASAP1-Controlled Signal Pathways to Inhibit Uveal Melanoma Metastasis

靶向 ASAP1 控制的信号通路抑制葡萄膜黑色素瘤转移

• 批准号: 10714245
• 负责人: Jae Hyuk Yoo
• 金额: $ 28.09万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-16 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714245
• 关键词: Ankyrin Repeat; Architecture; Binding; Biological Assay; Breast cancer metastasis; COUP transcription factor I; Cell Culture Techniques; Cell Nucleus; Cell membrane; Cells; Chromosome 3; Chromosomes; Country; Critical Pathways; Cytoplasmic Vesicles; Cytoskeleton; Data; Development; Disease; EMS1 gene; Exhibits; GNAQ gene; GTPase-Activating Proteins; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Growth; Human; In Vitro; Incidence; Invaded; Learning; Length; Liver; MAP Kinase Gene; Malignant Neoplasms; Mediating; Melanoma Cell; Metastatic Neoplasm to the Liver; Molecular; Molecular Target; Monomeric GTP-Binding Proteins; Monosomy; Mus; Mutation; Nebraska; Neoplasm Metastasis; Oncogenic; PH Domain; Pathway interactions; Patients; Persons; Process; Prognosis; Proliferating; Protein Kinase C; Proteins; Publishing; Research; Role; SH3 Domains; STAT4 gene; Signal Pathway; Signal Transduction; Testing; Transcription Factor AP-1; Tumor Promotion; Uveal Melanoma; Xenograft Model; Xenograft procedure; activating transcription factor 1; apoAI regulatory protein-1; beta catenin; cell motility; experimental study; human model; in vivo; inhibitor; insight; knock-down; malignant breast neoplasm; melanoma; mouse model; neoplastic cell; novel; novel strategies; overexpression; paxillin; pharmacologic; phospholipase C beta; pre-clinical; prevent; protein kinase C beta; trafficking; transcription factor; tumor; tumor progression; tumorigenesis; wound healing

Project Summary: "Targeting ASAP1-Controlled Signal Pathways to Inhibit Uveal Melanoma Metastasis" Uveal melanoma (UM) accounts for about 5% of all melanomas and has an incidence of 4-11 per million people per year in western countries. Although much has been learned about the signaling pathways that control UM oncogenesis, far less is known about the pathways that control metastatic disease. Preventing or effectively treating metastatic disease is critical because it occurs in about 50% of patients (most often in the liver) and once present, the prognosis is dismal. Amplification of chromosome 8q is one of the strong predictors of metastatic disease. ASAP1, which is located on chromosome 8q, has been shown to control metastasis in breast cancer. ASAP1 is amplified in about 40% of UM patients, and increased ASAP1 expression levels are associated with increased metastasis and poor prognosis. Overexpression of ASAP1 in low-grade tumor cells increases cell migration in an in vitro wound-healing assay. Furthermore, ASAP1 has been implicated in the metastasis of several cancers and is thought to promote metastasis by directly controlling the remodeling of the cytoskeletal architecture. We have recently begun to explore the molecular pathways that control uveal melanoma metastasis and have preliminary data showing that ASAP1 controls uveal melanoma cell invasion, proliferation, and metastasis in an orthotopic xenograft model of human uveal melanoma. Furthermore, we have identified several tumor-associated transcription factors, including STAT4, COUP-TF I, and COUP-TF II, that are activated by overexpression of ASAP1 in UM cells, suggesting a novel mechanism by which ASAP1 may also control UM metastasis. Therefore, we hypothesize that ASAP1 promotes uveal melanoma metastasis by activating signaling pathways that induce tumor-associated transcription factors and that inhibiting these pathways by pharmacologic inhibition will significantly reduce metastatic disease. We will test this hypothesis by pursuing two aims. In Aim 1, we will identify ASAP1 domain(s) that promote UM cell invasion and proliferation. These studies will involve expressing full-length ASAP1 and its serial deletion constructs following ASAP1 knockdown to determine the role of ASAP1 domains in UM cells. In Aim 2, we will assess the function of ASAP1-controlled transcription factor(s) in uveal melanoma cell invasion, proliferation, and tumor metastasis. Cell culture experiments will involve either knockdown of gene expression or pharmacological inhibition to determine the role of these transcription factors in UM cells. In vivo experiments will determine whether pharmacologic inhibition of ASAP1- activated transcription factors reduce tumor progression and metastasis in a xenograft model of human UM. For these studies, we will use JAK inhibitors and CIA1, which inhibit STAT4 and COUP-TF II, respectively. This research should provide us with new insights into the molecular mechanisms underlying metastatic spread of UM and may lead to novel approaches to prevent or treat metastatic UM.

项目总结：“靶向asap1控制的信号通路抑制葡萄膜黑色素瘤。