Systems Approach to the Biological Basis of Colon Cancer Metastases

描述(申请人提供)：结直肠癌(CRC)是美国癌症相关死亡的第三大原因。转移扩散是绝大多数死于实体瘤的患者的死亡原因，包括结直肠癌患者。尽管收集了大量关于人类肿瘤和转移模型的分子数据，但转移过程仍然知之甚少。我们的长期目标是使用综合系统生物学方法来研究结直肠癌转移的分子机制，以便开发新的策略来预测和治疗结直肠癌患者。 这一提议的中心假设如下：转移是相互关联的基因网络放松管制的功能性结果。我们认为，在基因共表达和蛋白质相互作用网络的背景下，可以通过分析明确定义的转移模型的基因表达谱来识别与转移相关的网络。具体目标是：1)识别与转移相关的网络模块，并对结直肠癌的生存做出基于模块的预测。2)推导、验证和确认存活预测模块转录调节因子的功能意义。3)基于网络的转移效应因子的优先排序和实验筛选。 建议的研究将提供关于结直肠癌转移网络机制的重要信息，并利用这些信息来改善患者预后和发现新的治疗靶点。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States. Metastatic spread is the cause of death for the vast majority of patients who die from solid tumors, including CRC patients. Notwithstanding the extensive molecular data collected on human tumors and metastatic models, the process of metastasis remains poorly understood. Our long-term goal is to use integrative systems biology approaches to investigate the molecular mechanisms that underlie CRC metastasis in order to develop new strategies for the prognosis and treatment of CRC patients. The central hypothesis for this proposal is as follows: Metastasis is the functional consequence of the deregulation of interconnected gene networks. We propose that metastasis-related networks can be identified by analyzing gene expression profiles from well-defined metastatic models within the context of gene co-expression and protein interaction networks. Specific aims are: 1) Identify metastasis-related network modules and make module-based predictions for CRC survival. 2) Derive, validate, and confirm functional significance of transcriptional regulators of survival-predictive modules. 3) Network-based prioritization and experimental screening of putative effectors of metastasis. The proposed studies will provide important information on the network mechanisms of CRC metastasis and use this information to improve patient prognosis and discover novel therapeutic targets.