Biological models of colorectal cancer metastasis and tumor suppression provide mechanistic insights to guide personalized care of the colorectal cancer patient

Abstract

Colorectal cancer is the second most lethal, non-cutaneous epithelial cancer in the United States. Metastasis contributes to the majority of cancer-related deaths in this disease. Metastasis closely resembles the developmental process of epithelial-mesenchymal transition (EMT) and reliable models to recapitulate this process can be useful to shed light onto the biology and prognosis of patients with colorectal cancer. Herein we describe a mouse model that led to the discovery of a gene signature of metastasis using comparative functional genomics, which identified stage II and III colon cancer patients prone to recurrence and death from metastatic disease, in addition to a low-risk sub-group of stage III patients for whom adjuvant chemotherapy provided no additional survival benefit. These findings form the basis for substantive pre-clinical biomarker testing and eventual translational application to a clinical trial. On the other hand, loss of tumor suppressor genes affects the majority of colorectal cancer patients to permit progression of disease. Many pathways are defective in the pathogenesis of colorectal cancer; however, more than half of the patients have defects in the Wnt/β-catenin and Transforming Growth Factor-β (TGFβ) signaling pathways which are critical for development and intestinal homeostasis. This body of work also uses in vitro and in vivo models to describe a new role for the tumor suppressor Smad4 in the repression of β-catenin transcriptional activity in epithelial cells. This repression was associated with down-regulation of Wnt signaling and reversal of EMT. Clinical relevance of this effect was demonstrated by an epithelial cell-specific, Smad4-modulated gene expression profile associated with Wnt signaling suppression, which contributed prognostic information for colorectal cancer patients independently of pathological staging. These findings should facilitate hypothesis testing for biologically-targeted therapeutic interventions based on TGFβ/Smad and Wnt/β-catenin pathway activity levels. Overall, these results provide insight into the biology of metastasis and tumor suppression in colorectal cancer to promote seamless translation to care of the colorectal cancer patient at the bedside.