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

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%

项目成果

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JAMES WILLIAM HARBOUR其他文献

JAMES WILLIAM HARBOUR的其他文献

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{{ truncateString('JAMES WILLIAM HARBOUR', 18)}}的其他基金

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:
    10675515
  • 财政年份:
    2021
  • 资助金额:
    $ 68.43万
  • 项目类别:
Diversity Supplement for Molecular Predictive Testing in Ocular Melanoma
眼部黑色素瘤分子预测测试的多样性补充
  • 批准号:
    10220448
  • 财政年份:
    2020
  • 资助金额:
    $ 68.43万
  • 项目类别:
3-Dimensional Retinal Organoid Platform for the Study of Retinoblastoma
用于视网膜母细胞瘤研究的 3 维视网膜类器官平台
  • 批准号:
    10447198
  • 财政年份:
    2020
  • 资助金额:
    $ 68.43万
  • 项目类别:
3-Dimensional Retinal Organoid Platform for the Study of Retinoblastoma
用于视网膜母细胞瘤研究的 3 维视网膜类器官平台
  • 批准号:
    10657628
  • 财政年份:
    2020
  • 资助金额:
    $ 68.43万
  • 项目类别:
3-Dimensional Retinal Organoid Platform for the Study of Retinoblastoma
用于视网膜母细胞瘤研究的 3 维视网膜类器官平台
  • 批准号:
    10263901
  • 财政年份:
    2020
  • 资助金额:
    $ 68.43万
  • 项目类别:
MOLECULAR PREDICTIVE TESTING IN OCULAR MELANOMA
眼部黑色素瘤的分子预测测试
  • 批准号:
    7953938
  • 财政年份:
    2009
  • 资助金额:
    $ 68.43万
  • 项目类别:
MOLECULAR PREDICTIVE TESTING IN OCULAR MELANOMA
眼部黑色素瘤的分子预测测试
  • 批准号:
    7721521
  • 财政年份:
    2008
  • 资助金额:
    $ 68.43万
  • 项目类别:
Molecular Predictive Testing in Ocular Melanoma
眼部黑色素瘤的分子预测测试
  • 批准号:
    7250878
  • 财政年份:
    2006
  • 资助金额:
    $ 68.43万
  • 项目类别:
Molecular Predictive Testing in Ocular Melanoma
眼部黑色素瘤的分子预测测试
  • 批准号:
    9902342
  • 财政年份:
    2006
  • 资助金额:
    $ 68.43万
  • 项目类别:
Molecular Predictive Testing in Ocular Melanoma
眼部黑色素瘤的分子预测测试
  • 批准号:
    7467990
  • 财政年份:
    2006
  • 资助金额:
    $ 68.43万
  • 项目类别:

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