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Characterization and targeting of the epigenetic state underlying uveal melanoma liver metastasis

葡萄膜黑色素瘤肝转移表观遗传状态的表征和靶向

基本信息

批准号：
10298599
负责人：
JAMES WILLIAM HARBOUR
金额：
$ 68.43万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
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：
2021-08-09 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298599
关键词：
ATAC-seq Address Adjuvant Adoption Alleles Animal Model Automobile Driving Binding Sites CRISPR screen Cells Chromatin Clinical Clinical Trials Data Data Set Dependence Development Diagnosis Disease Drug resistance Environment Epigenetic Process FGF2 gene Fostering GDF15 gene GNAQ gene Gene Expression Gene Expression Profiling Genes Genetic Genetic Predisposition to Disease Genetic Transcription Goals Grant Growth HDAC1 gene Hepatic Stellate Cell Histone Deacetylase IL8 gene Knowledge Liver MAP Kinase Gene MEK inhibition Maintenance Mediating Melanoma Cell Metastatic Neoplasm to the Liver Modeling Molecular Mus Mutation Neoplasm Metastasis Oncogenic Output Pathway interactions Patients Phenotype Program Sustainability Proteomics Risk Role Signal Pathway Signal Transduction Signaling Molecule Specimen Subgroup TP53 gene Testing Therapeutic Time Up-Regulation Uveal Melanoma Vascular Endothelial Growth Factors Xenograft Model angiogenesis base combinatorial epigenomics high risk innovation jun Oncogene knock-down malignant neoplasm of eye melanocyte multiple omics mutant novel novel strategies novel therapeutic intervention prevent programs senescence single-cell RNA sequencing small molecule inhibitor targeted treatment therapy resistant transcription factor treatment strategy tumor progression

项目摘要

Uveal melanoma (UM) is a highly aggressive and frequently fatal cancer of the eye. While only 2-4% of patients will have detectable metastases at diagnosis, up to 50% of patients later develop metastatic disease, overwhelmingly localized to the liver. Gene expression profiling separates UM to into two sub-groups, low risk Class 1 UM and high risk Class 2 UM. Almost all UMs harbor an initiating mutation in the Gαq signaling pathway, most commonly in GNAQ. Class 2 UMs harbor “progression mutations” in one of several genes that drive tumor progression, the most common being BAP1. Previous studies from our group identified biallelic inactivation of BAP1 as the strongest predictor of liver metastasis in UM. However, the cellular and molecular mechanisms underlying liver metastasis in UM remain undetermined. This gap in our knowledge limits our ability to develop effective adjuvant treatment for high risk patients and systemic treatments for disseminated disease. Gαq signaling activates the MAPK pathway in UM cells, and our preliminary single cell data show that Gαq- mutant UMs are enriched for FOS/JUN transcriptional states. Loss of BAP1 function was associated with escape from senescence, and a de-differentiated phenotype in UM cells that allowed their interaction with hepatic stellate cells, leading to progression of liver metastases and drug resistance. The dedifferentiated state of UM cells was specifically dependent on HDAC1, with HDAC inhibition restoring the differentiated state of UM cells, and increasing the efficacy of MEK inhibition in UM liver metastasis models. The overarching goal of this grant is to define the mechanism by which mutant Gαq and BAP1 loss co-operate to drive UM liver metastasis development. In Aim 1 we will define how BAP1 loss alters the signaling, transcriptional and epigenetic state of Gαq-mutant UM cells to allow senescence to be overcome. In Aim 2, we will address how the cellular state of Gαq-mutant/BAP1-loss UM activates hepatic stellate cells to generate a pro-survival niche in the liver through increased angiogenesis and upregulation of MAPK signaling. In Aim 3, we will explore the HDAC1 dependency of the Gαq-BAP1 loss UM cell state and will validate hits from recent CRISPR screens to identify novel therapeutic approaches to treat UM liver metastases, that we will validate in animal models. At completion of this study, we expect to have defined new approaches to prevent and treat UM liver metastases, that we will explore in clinical trials.

葡萄膜黑色素瘤（UM）是一种高度侵袭性和经常致命的眼部癌症。而只有2% -4%