CYLD-a potential mediator of site-specific melanoma metastasis

CYLD-位点特异性黑色素瘤转移的潜在介质

• 批准号: 257889060
• 负责人: Professorin Dr. Anja-Katrin Bosserhoff
• 金额: --
• 依托单位: Lehrstuhl für Biochemie und Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/257889060?language=en
• 关键词: CYLD; potential; mediator; site; specific

Unlike in cylindromatosis, downregulation of the de-ubiquitinase CYLD in melanoma, a highly aggressive tumour, is not caused by mutations in the CYLD gene but rather by a constitutive and high expression of the transcription factor SNAIL 1. The reduced CYLD level leads to BCL-3/p50/p52-dependent NFκB activation, which in turn triggers expression of genes such as cyclinD1 and N-cadherin. Elevated levels of cyclinD1 and N-cadherin promote melanoma proliferation and invasion. Importantly, in melanoma patients we could link the loss of CYLD expression to Clark level, tumour thickness, and progression free and overall survival. In further experiments, we generated a Cyld-deficient mouse on the background of a melanoma-prone mouse model (Grm1-transgene), a model for spontaneously developing melanoma with 100% penetrance. Grm1/Cyld+/+ mice show no dermal or local invasion whereas Grm1/Cyld-/- mice present multiple local skin metastases and invasion into the muscle. In the project we intend to further exploit this mouse model and we aim to determine the impact of CYLD in efficient local metastasis and would like to transfer our new knowledge also to the event of distal site-specific metastasis, especially in liver, brain and lymph nodes. Regarding this we are interested to discover the invasive routes (e.g. lymphatic pathways), which are taken by the tumour cells and want to differentiate between molecular changes, which have an impact on the tumour cells themselves, and CYLD-dependent factors, which change the micro-environment (e.g. mast cells). We have performed RNA-Seq analysis of the tissue samples of nevi and primary tumours of both mice model subtypes. We will now characterize epigenetic regulation mechanisms, which are relevant for differences in metastatic behaviour. Furthermore, we will analyse miRNA expression and changes in murine tissue samples of the mouse model and murine cell lines, which we generated in the first funding period.

与圆柱瘤病不同，黑色素瘤（一种高度侵袭性肿瘤）中去泛素化酶CYLD的下调不是由CYLD基因突变引起的，而是由转录因子SNAIL 1的组成性和高表达引起的。CYLD水平降低导致BCL-3/p50/p52依赖性NFκB活化，进而触发基因如cyclinD 1和N-cadherin的表达。cyclinD 1和N-cadherin水平升高促进黑色素瘤增殖和侵袭。重要的是，在黑色素瘤患者中，我们可以将CYLD表达的丧失与Clark水平、肿瘤厚度、无进展生存期和总生存期联系起来。在进一步的实验中，我们在黑色素瘤易感小鼠模型（Grm 1-转基因）的背景下产生了Cyld缺陷小鼠，所述黑色素瘤易感小鼠模型是具有100%转移率的自发发展的黑色素瘤的模型。Grm 1/Cyld+/+小鼠没有表现出真皮或局部侵袭，而Grm 1/Cyld-/-小鼠表现出多处局部皮肤转移和肌肉侵袭。在该项目中，我们打算进一步利用这种小鼠模型，我们的目标是确定CYLD对有效局部转移的影响，并希望将我们的新知识转移到远端位点特异性转移的事件中，特别是在肝脏、大脑和淋巴结中。关于这一点，我们有兴趣发现肿瘤细胞所采取的侵入性途径（例如淋巴途径），并希望区分对肿瘤细胞本身有影响的分子变化和改变微环境（例如肥大细胞）的CYLD依赖性因子。我们已经对两种小鼠模型亚型的痣和原发性肿瘤的组织样品进行了RNA-Seq分析。我们现在将表征表观遗传调控机制，这是相关的转移行为的差异。此外，我们将分析我们在第一个资助期产生的小鼠模型和小鼠细胞系的小鼠组织样本中的miRNA表达和变化。