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

• 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
• 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

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)是一种高度侵袭性且经常致命的眼癌。而只有2%-4%的 患者在确诊时会有可检测到的转移，高达50%的患者后来会发展为转移疾病， 压倒性地局限于肝脏。基因表达谱将UM TO分为两个亚组，风险较低 1级UM和高风险2级UM。几乎所有的UM都含有G-α-Q信号的起始突变 途径，最常见的是在GNAQ。2类UM在以下几个基因中的一个中存在“进行性突变” 推动肿瘤进展，最常见的是BAP1。我们小组之前的研究确定了双等位基因 BAP1失活是UM肝转移的最强预测因子。然而，细胞和分子 UM肝转移的机制尚不清楚。我们知识上的这种差距限制了我们 有能力为高危患者开发有效的辅助治疗，并为播散性疾病开发系统治疗 疾病。 GαQ信号在UM细胞中激活MAPK通路，我们的初步单细胞数据显示GαQ- 突变um富含fos/jun转录状态。BAP1功能的丧失与 在UM细胞中逃脱衰老和去分化的表型，允许它们与 肝星状细胞，导致肝转移的进展和耐药。去分化状态 UM细胞的分化依赖于HDAC1，抑制HDAC1可恢复UM细胞的分化状态 UM细胞，并提高MEK抑制UM肝转移模型的疗效。的首要目标是 这项拨款是为了确定突变的GαQ和BAP1丢失共同驱动UM肝的机制 转移的发展。在目标1中，我们将定义BAP1缺失如何改变信号、转录和 GαQ突变UM细胞的表观遗传状态使衰老得以克服。在目标2中，我们将解决如何 GαQ突变体/BAP1缺失UM的细胞状态激活肝星状细胞产生有利于生存的利基 在肝脏中，通过增加血管生成和上调MAPK信号通路。在目标3中，我们将探索 GαQ-BAP1丢失UM单元状态的HDAC1依赖性，并将验证来自最近CRISPR筛查的命中以 确定治疗UM肝转移的新的治疗方法，我们将在动物模型中进行验证。在… 这项研究的完成，我们预计将定义新的方法来预防和治疗UM肝转移， 我们将在临床试验中进行探索。