A nutrient-sensing pathway activated in APC-driven colorectal cancer Open Access

Truncating mutations in the tumour suppressor gene encoding APC are the most common cause of colorectal cancer. APC is a negative regulator of the Wnt signalling pathway, and constitutive activation of Wnt–β-catenin signalling is thought to form the basis of the oncogenic effects of APC mutations. However, recent evidence has suggested that other proteins could also be involved. Alexander Valvezan, Peter Klein and colleagues recently showed that APC suppresses mTORC1 activity in vitro. Here, the group explored the relationship between APC and mTORC1, a nutrient sensor that regulates cell growth and proliferation, in vivo. The authors show that mTORC1 activity is markedly upregulated in apc mutant zebrafish and in intestinal polyps in Apc mutant mice. mTORC1 inhibition suppressed multiple developmental defects caused by apc mutation in zebrafish. Interestingly, combined inhibition of mTORC1 and Wnt signalling was needed to restore normal body curvature. These findings suggest that mTORC1 is a key mediator of APC-driven tumorigenesis and developmental defects, and suggest mechanistic overlap with other polyposis syndromes that are associated with mTORC1 activation. Page 63