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：
10675515
负责人：
JAMES WILLIAM HARBOUR
金额：
$ 63.84万
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/10675515
关键词：
ATAC-seq Adjuvant Therapy 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 Induction Signal Pathway Signal Transduction Signaling Molecule Specimen Subgroup TP53 gene Testing Therapeutic Time Up-Regulation Uveal Melanoma Vascular Endothelial Growth Factors Xenograft Model angiogenesis 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 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.

卵子黑色素瘤（UM）是眼睛高度侵略性且经常致命的癌症。虽然只有2-4％患者将在诊断时检测到转移量，多达50％的患者后来出现转移性疾病，绝大多数位于肝脏。基因表达分析将UM分为两个亚组，低风险 1级UM和高风险类别2 UM。几乎所有的UM都藏有GαQ信号中的启动突变途径，最常见于GNAQ。 2类UMS港口“进步突变”中的几个基因之一驱动肿瘤进展，最常见的是BAP1。我们小组的先前研究确定了生物素 BAP1作为UM中肝转移的强烈预测指标。但是，细胞和分子 UM中肝转移的基础机制仍然不确定。我们的知识差距限制了我们的能够为高风险患者和全身治疗的有效调整治疗疾病。 GαQ信号传导激活UM细胞中的MAPK途径，我们的初步单细胞数据表明GαQ- 突变体UM富含FOS/JUN转录状态。 BAP1功能的损失与逃脱感应，在UM细胞中脱离分化的表型，使它们与之相互作用肝炎星状细胞，导致肝转移和耐药性的进展。去分化状态 UM细胞的特异性取决于HDAC1，HDAC抑制作用恢复了分化状态 UM细胞，并提高UM肝转移模型中MEK抑制的效率。总体目标该赠款是定义突变GαQ和BAP1损失合作以驱动UM肝脏的机制转移发展。在AIM 1中，我们将定义BAP1损失如何改变信号，转录和 GαQ突变的UM细胞的表观遗传状态可以克服感受。在AIM 2中，我们将解决如何 GαQ-突变剂/BAP1-loss UM的细胞状态激活肝星状细胞产生生存的生存生态位在AIM 3中，我们将通过增加的MAPK信号传导的血管生成和上调来探索肝脏。 GαQ-BAP1损耗UM细胞状态的HDAC1依赖性，并将验证从最近的CRISPR屏幕到确定新型热方法治疗UM肝转移，我们将在动物模型中验证。完成这项研究的完成，我们希望已经定义了预防和治疗UM肝转移的新方法，我们将在临床试验中探索。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

HDAC11 activity contributes to MEK inhibitor escape in uveal melanoma.

DOI：
10.1038/s41417-022-00452-7
发表时间：
2022-12
期刊：
CANCER GENE THERAPY
影响因子：
6.4
作者：
Sriramareddy, Sathya Neelature;Faiao-Flores, Fernanda;Emmons, Michael F.;Saha, Biswarup;Chellappan, Srikumar;Wyatt, Clayton;Smalley, Inna;Licht, Jonathan D.;Durante, Michael A.;Harbour, J. William;Smalley, Keiran S. M.
通讯作者：
Smalley, Keiran S. M.