Epigenetics of Melanoma Metastasis

描述(申请人提供)：恶性黑色素瘤是一种高度侵袭性的疾病，死亡率高得惊人。虽然我们已经对黑色素瘤的遗传决定因素有了实质性的了解，但我们对黑色素瘤转移的表观遗传学机制的了解非常有限。因此，这项建议旨在确定表观遗传修饰和参与转移过程的因素，并了解它们如何赋予癌细胞转移潜力。长期目标是能够识别新的药物靶点并开发诊断分析方法。在我之前的培训中，我在研究结肠癌发生和启动过程中的表观遗传机制方面积累了一些经验。我热衷于使用黑色素瘤系统解决这个关键问题的一些经验。Chin实验室在利用基因组数据集和大规模筛查了解转移以及多种黑色素瘤小鼠模型的可用性方面的专业知识为我提供了一个完美的环境来解决我感兴趣的科学问题。在这项提议中，我的目标是利用新的表观基因组学方法、强大的体内筛选和小鼠模型来了解黑色素瘤细胞促转移特性的表观遗传学机制。在目标1中，我将阐明RNF2促转移作用的机制，并评估其作为药物靶点的潜力。在目标2中，我将确定非转移细胞和转移前细胞的表观基因组图，以努力识别受转移前表观遗传学变化影响的细胞系统。在目标3中，我将采取公正的方法，在小鼠体内使用大规模筛查来识别表观遗传转移的促进者和抑制者。我们将研究在目标1和目标2中用于RNF2的“点击”屏幕的机制。总的来说，我在表观基因组学方法、小鼠建模和大规模活体筛选方面的培训将磨练我的科学技能，为我成功的独立职业生涯做好准备。在我的独立阶段，我将确定新的转移机制-建议筛查确定的抑制和启动子。此外，我还将建立小鼠和斑马鱼模型，以评估这些基因作为药物靶点的能力。最后，通过这些研究，我希望确定具有表观遗传学作用的新的药物靶点和可能的表观遗传学标记(在特定的基因组座位上)，用于设计新的诊断方法。 公共卫生相关性：在这项提案中，我们的目标是研究各种表观遗传蛋白和标记如何单独或联合改变黑色素瘤细胞的基因组状态，以传递转移能力。这项工作将揭示治疗恶性黑色素瘤的潜在新药靶点。此外，我们的表观基因组分析将揭示一组基因/区域，其表观遗传状态可能被用于设计新的诊断方法来评估肿瘤的转移潜力。

DESCRIPTION (provided by applicant): Malignant melanoma is a highly aggressive disease with alarmingly high mortality rates. Although we have gained substantial understanding of genetic determinants of the melanoma, we have very limited knowledge of epigenetic mechanisms underlying melanoma metastasis. Therefore, this proposal aims to identify epigenetic modifications and factors involved in the process of metastasis and understand how they impart metastatic potential to cancer cells. The long term-goal is to be able to identify novel drug targets and develop diagnostic assays. During my previous training, I have gained some experience in studying epigenetic mechanisms during development and colon cancer initiation. I am keen to apply some of this experience in addressing this vital question using melanoma system. The Chin lab's expertise in utilizing genomic datasets and large scale screens to understand metastasis and the availability of multiple mouse models of melanoma provides me a perfect environment to address the scientific question of my interest. In this proposal I aim to understand epigenetic mechanisms underlying pro-metastatic properties of melanoma cells utilizing new epigenomic methods, powerful in vivo screens and mouse models. In Aim 1, I will elucidate the mechanism of the pro- metastatic action of RNF2 and assess its potential as a drug target. In Aim 2, I will determine the epigenomic landscape of non-metastatic cells and pro-metastatic cells in an effort to identify the cellular systems affected by pro-metastatic epigenetic changes. In Aim 3, I will take unbiased approach and use in vivo large scale screens in mice to identify epigenetic metastasis-promoters and suppressors. The mechanism for the 'hits' from this screen will be studied as used for RNF2 in Aim 1 and 2. Overall, my training in epigenomic methods, mouse modeling and large scale in vivo screens will hone my scientific skills to prepare me for a successful independent career. In my independent phase, I will identify the mechanism of new metastasis-suppressors and promoters identified by proposed-screens. In addition, I will build mouse and zebrafish models to assess the ability of these genes as drug targets. In the end, by these studies I hope to identify new drug targets with epigenetic roles and possible epigenetic marks (on specific genomic loci) to use for devising new diagnostic methods. PUBLIC HEALTH RELEVANCE: In this proposal, we aim to investigate how various epigenetic proteins and marks, alone or in combination, change the genomic state of melanoma cells to impart metastatic capacity. This work will reveal potential new drug targets for treatment of malignant melnoma. Also, our epigenomic analyses will reveal a set of genes/regions, whose epigenetic status may be used to devise new diagnostic assays for assessing metastatic potential of tumors.