Systems Approach to the Biological Basis of Colon Cancer Metastases

描述（由申请人提供）：结直肠癌（CRC）是美国癌症相关死亡的第三大原因。 转移性扩散是绝大多数死于实体瘤的患者（包括CRC患者）的死亡原因。 尽管在人类肿瘤和转移模型上收集了大量的分子数据，但对转移的过程仍然知之甚少。 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，以便为结直肠癌患者的预后和治疗制定新的策略。 这个提议的中心假设如下：转移是相互关联的基因网络失调的功能后果。 我们建议，转移相关的网络可以通过分析基因表达谱从定义明确的转移模型的背景下，基因共表达和蛋白质相互作用的网络。 具体目标是：1）识别与转移相关的网络模块，并基于模块对CRC生存进行预测。2)推导，验证，并确认生存预测模块的转录调节因子的功能意义。3)基于网络的优先级排序和转移的假定效应子的实验筛选。 拟议的研究将提供有关CRC转移网络机制的重要信息，并利用这些信息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.