The molecular aetiology of colorectal cancer (CRC) is well known: the mutant, oncogenic form of the Wnt signaling pathway drives the malignant transformation of intestinal epithelial stem cells leading to tumorigenesis. The primary research interests of the lab are to uncover regulatory nodes within oncogenic Wnt signaling in order to establish therapeutic entry points.
At the core of the research programme are two tractable models of CRC to analyze roles for cellular signaling pathways, in particular the oncogenic Wnt signaling pathway. One of these models is a genetically engineered mouse (GEM) to model CRC, a disease that currently lacks good in vivo models. Importantly, this GEM encompasses the genetically coded ability to inducibly inhibit oncogenic Wnt signaling in tumours.
The second model is the establishment of a CRC stem cell culture system in collaboration with the laboratory of Dr. Ashraf Ibrahim, a clinical histopathologist at Addenbrookes Hospital. This will provide an in vitro assay system to examine the maintenance of the ‘cancer stem cell state’ by cellular signaling pathways (such as Wnt, Notch, Hh/Gli and MAPK) using genetic and chemical loss-of-function.
We are also interested in the functions of tankyrase, a protein that covalently modifies proteins with poly(ADP-ribose) chains. PARylation is a post-translational modification carried out by a battery of 17 PARylase enzymes with diverse biological functions. Tankyrase itself regulates Wnt signaling, the insulin-responsive GLUT4 glucose transporter, telomerase elongation and has roles in cytokinesis. We are examining compelling links between these functions and their impact on the physiology of CRC cells.
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