Truncating mutations in adenomatous polyposis coli (APC) are
strongly linked to colorectal cancers. APC is a negative regulator of
the Wnt pathway and constitutive Wnt activation mediated by
enhanced Wnt–β-catenin target gene activation is believed to be the
predominant mechanism responsible for APC mutant phenotypes.
However, recent evidence suggests that additional downstream
effectors contribute to APC mutant phenotypes. We previously
identified a mechanism in cultured human cells by which APC, acting
through glycogen synthase kinase-3 (GSK-3), suppresses mTORC1,
a nutrient sensor that regulates cell growth and proliferation. We
hypothesized that truncating Apc mutations should activate mTORC1
in vivo and that mTORC1 plays an important role in Apc mutant
phenotypes. We find that mTORC1 is strongly activated in apc
mutant zebrafish and in intestinal polyps in Apc mutant mice.
Furthermore, mTORC1 activation is essential downstream of APC as
mTORC1 inhibition partially rescues Apc mutant phenotypes
including early lethality, reduced circulation and liver hyperplasia.
Importantly, combining mTORC1 and Wnt inhibition rescues defects
in morphogenesis of the anterior-posterior axis that are not rescued
by inhibition of either pathway alone. These data establish mTORC1
as a crucial, β-catenin independent effector of oncogenic Apc
mutations and highlight the importance of mTORC1 regulation by
APC during embryonic development. Our findings also suggest a new
model of colorectal cancer pathogenesis in which mTORC1 is
activated in parallel with Wnt/β-catenin signaling.