Wnt activating mechanisms in colorectal cancer


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Vivian Li1,
1Medical Research Council (MRC) National Institute for Medical Research, London, UK

Abstract

Wnt signalling pathways play essential roles in embryonic development and tissue homeostasis. Aberrant activation of Wnt signalling is the primary cause of colorectal cancer (CRC). Loss of function of adenomatous polyposis coli (APC) is a key step to initiate adenoma formation through constitutive Wnt activation. Despite the crucial role of Wnt/APC in tumour initiation, limited drug targets or inhibitors of Wnt pathway have been developed nowadays due to the unclear mechanism of how APC truncation activates Wnt pathways. We have previously redefined the Wnt activation model in the physiological state, and have further demonstrated the failure of b-catenin ubiquitination in APC-mutated cells as the principal deregulated event upon APC mutation. It still remains unclear how APC mediates b-catenin ubiquitination in the destruction complex. One of our research focuses is to characterise the APC regulatory role in b-catenin ubiquitination to gain better insight of Wnt pathway activation in CRC. We also study the efficacy and efficiency of the current available Wnt inhibitors in CRC cells and organoids by generating specific Crispr-targeted mutations. We aim to identify specific drug targets by understanding the Wnt activating mechanism in CRC.

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