The Role of CDK5 in Metastasis

描述(申请人提供)：转移是许多类型癌症最相关的负面预后指标之一。我们推测，在大脑新皮质发育过程中控制神经元迁移的CDK5活性，也可能控制某些癌症的转移。我们发现，迄今为止被认为主要在神经元谱系中活跃的CDK5，由于其激活蛋白p35的表达，在几种类型的癌症中都是活跃的。阻断CDK5活性会抑制癌细胞的运动和侵袭，在前列腺癌模型中，自发转移减少79%。提示CDK5活性可能是肿瘤转移的中枢控制因素，CDK5可能成为限制肿瘤转移的潜在治疗靶点。本研究将探讨CDK5在肿瘤转移中的作用及其在肿瘤生物学中的作用。在具体目标1中，将建立CDK5在转移和肿瘤生物学中的作用的基因工程动物模型。CDK5消融对肿瘤生长、分化、血管生成、免疫反应，特别是转移的影响将被研究。潜在的途径逃脱CDK5消融介导的转移抑制将被探索。在特定目的2中，通过对前列腺癌中CDK5抑制的基因表达分析，探讨CDK5在肿瘤中的作用。先进的生物统计分析方法将被应用于微阵列基因表达数据，以寻找可能预测转移控制机制的转录信号，以及CDK5在肿瘤生物学中的新功能，以及对其他治疗的潜在增敏。数据分析方法将包括GSEA、贝叶斯分解和其他分析工具，包括奥克斯博士团队正在开发的分析方法。功能生物学分析将被用来证实从这些转录签名分析中得出的预测。在具体目标3中，将探讨受体酪氨酸激酶控制p35表达的机制。我们将确认ErbB家族介导的p35的激活处于转录水平，然后确定介导这一诱导的转录因子(S)。我们将利用基因转移和siRNA来检测已鉴定的转录因子对p35表达的影响。确定的转录因子的表达与p35表达的相关性将在一组细胞系中进行检验。简介：在许多类型的癌症中，转移扩散与致命性密切相关，控制转移可能是提高生存率的重要一步。我们已经确定了一种细胞酶CDK5，它的活性似乎是前列腺癌和其他癌症转移所必需的。这个项目试图确定CDK5，一个潜在的治疗靶点，在控制转移和肿瘤功能方面的作用。

DESCRIPTION (provided by applicant): Metastasis is one of the most relevant negative prognostic indicators for many types of cancer. We hypothesized that CDK5 activity, which controls neuronal migration during brain neocortical development, also may control metastasis in some cancers. We have found that CDK5, heretofore thought to be active mainly in neuronal lineages, is active in several types of cancer, due to expression of its activator protein p35. Blocking CDK5 activity resulted in inhibition of cancer cell motility and invasion, and, in a prostate cancer model, a 79% decrease in spontaneous metastasis. This indicates that CDK5 activity may be a central control for metastasis, and CDK5 may be a potential therapeutic target to limit metastasis. This application will explore the role of CDK5 in metastasis, and its function in the biology of cancer. In Specific Aim 1, a genetically engineered animal model for the role of CDK5 in metastasis and tumor biology will be developed. The effect of Cdk5 ablation on tumor growth, differentiation, angiogenesis, immune response, and, especially, metastasis will be investigated. Potential pathways for escape from Cdk5 ablation-mediated inhibition of metastasis will be explored. In Specific Aim 2, the functions of CDK5 in cancer will be explored, using gene expression analysis of CDK5 inhibition in prostate cancer. Advanced biostatistical analysis methods will be applied to microarray gene expression data, to look for transcription signatures that may predict mechanisms of control of metastasis, as well as novel functions of Cdk5 in tumor biology, and potential sensitization to other therapies. Data analysis methods will include GSEA, Bayesian Decomposition, and other analytical tools, including analytical methods under development in Dr. Ochs's group. Functional biological analyses will be employed to confirm predictions derived from these analyses of transcriptional signatures. In Specific Aim 3, the mechanism of receptor tyrosine kinase control of p35 expression will be explored. We will confirm that ErbB-family mediated activation of p35 is at the transcriptional level, and then identify the transcription factor(s) that mediate this induction. The effect of the identified transcription factor on p35 expression will be examined, using gene transfer and siRNA. The correlation of expression of the identified transcription factor with p35 expression will be examined in a panel of cell lines. Narrative: In many types of cancer, metastatic spread is closely linked to lethality, and control of metastasis may be an important step in increasing survival. We have identified a cellular enzyme, CDK5, whose activity appears to be required for metastasis in prostate and other cancers. This project seeks to define the role of CDK5, a potential therapeutic target, in control of metastasis and tumor function.