Inhibition of the Wnt Receptor Complex by the Tumor Suppressor Adenomatous Polyposis Coli

Project Summary
Inhibition of Wnt Receptor Activation by the Tumor Suppressor Adenomatous Polyposis Coli
The long-term objective of this study is to investigate how the tumor suppressor Adenomatous
polyposis coli (APC) inhibits the Wnt signal transduction pathway by regulating the Wnt receptor
complex (signalosome) and to demonstrate how this can be exploited to target APC mutant colorectal
cancers (CRCs). Wnt signaling is essential for intestinal stem cell maintenance, whereas aberrant
activation of this pathway, which occurs most frequently through mutational inactivation of APC, triggers
the development of the vast majority of CRCs. In the classical model for Wnt signaling, the sole role of
APC is to destabilize the key transcriptional activator in the Wnt pathway, beta-catenin. However, our
recently published findings reveal an additional and entirely new function – APC prevents the
internalization and consequent activation of the signalosome, a novel role that is evolutionarily
conserved. We have shown that: 1) inducible loss of APC is rapidly followed by ligand-independent
signalosome activation; 2) depletion or antibody-mediated inhibition of LRP6 (a signalosome
component) inhibits the stabilization of beta-catenin, the transcriptional activation of Wnt target genes,
and the proliferation of APC mutant cells; and 3) in APC mutant cells, endocytosis of Wnt receptors is
required for the aberrant activation of Wnt signaling. The goal of this project is to use in vitro, ex vivo,
and in vivo approaches to gain a better understanding of how APC inhibits signalosome activation
under physiological conditions and to determine how aberrant activation of the signalosome underlies
the consequences of APC inactivation in tumors. The three specific aims are to: 1) elucidate the
mechanism by which APC loss promotes signalosome assembly in CRC cells; 2) identify the APC
mutant CRC cells most susceptible to LRP6 inactivation; and 3) test the efficacy of LRP6 inactivation
on CRC tumorigenicity in vivo. Because the molecular mechanisms by which APC prevents the
aberrant activation of Wnt signaling are important for our understanding of colorectal carcinogenesis,
the knowledge gained from this study will aid in the development of new therapeutic strategies for the
treatment of CRC and other Wnt-driven cancers.

Grant Number: 5R01CA244188-05
NIH Institute/Center: NIH
Principal Investigator: Yasmath Ahmed