Metastatic recurrence is the leading cause of cancer death in patients with colorectal carcinoma. In order to capture the molecular underpinnings for metastasis and tumor progression, we performed integrative network analysis on 11 independent colorectal cancer gene expression data sets and applied expression data from an immuncompetenet mouse model of metastasis as an additional filter for this biological process. In silico analysis of one metastasis-related co-expression module predicted Nuclear Factor of Activated T-cell (NFAT) transcription factors as potential regulators for the module. Cells selected for invasiveness and metastatic capability expressed higher levels of NFATc1 as compared with poorly metastatic and less invasive parental cells. We found that inhibition of NFATc1 in human and mouse colon cancer cells resulted in decreased invasiveness in culture and down-regulation of metastasis-related network genes. Overexpression of NFATc1 significantly increased the metastatic potential of colon cancer cells while inhibition of NFATc1 reduced metastasis grown in an immunocompetent mouse model. Finally, we found that an 8-gene signature comprising genes up-regulated by NFATc1 significantly correlated with worse clinical outcomes in stage II and III colorectal cancer patients. Thus, NFATc1 regulates colon cancer cell behavior and its transcriptional targets constitute a new, biologically-anchored gene expression signature for the identification of colon cancers with high risk of metastatic recurrence.