Systems Approach to the Biological Basis of Colon Cancer Metastases

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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.