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。我们假设，在大脑新皮层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也有活性。阻断CDK5活性导致癌细胞运动和侵袭受到抑制，并且在前列腺癌模型中，自发转移减少79%。这表明CDK5活性可能是转移的中心控制，CDK5可能是限制转移的潜在治疗靶点。本应用将探讨CDK5在肿瘤转移中的作用及其在肿瘤生物学中的功能。在Specific Aim 1中，将开发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。我们将探索从Cdk5消融介导的转移抑制中逃脱的潜在途径。在Specific Aim 2中，我们将通过对前列腺癌中CDK5抑制的基因表达分析来探讨CDK5在癌症中的功能。先进的生物统计学分析方法将应用于微阵列基因表达数据，寻找可能预测转移控制机制的转录特征，以及Cdk5在肿瘤生物学中的新功能，以及对其他疗法的潜在敏感性。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。功能生物学分析将用于证实从这些转录特征分析中得出的预测。在Specific Aim 3中，我们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激活是在转录水平，然后确定介导这种诱导的转录因子。鉴定的转录因子对p35表达的影响将通过基因转移和siRNA进行检测。鉴定的转录因子表达与p35表达的相关性将在细胞系面板中进行检查。叙述：在许多类型的癌症中，转移性扩散与致死率密切相关，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，其活性似乎是前列腺癌和其他癌症转移所必需的。该项目旨在确定CDK5在控制转移和肿瘤功能中的作用，这是一个潜在的治疗靶点。

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.