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 suitable 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 role of the tumour suppressor adenomatous polyposis coli (APC) in CRC etiology. In addition to Wnt pathway regulation, APC plays a key role in maintaining epithelial cell polarity. Mutational inactivation of APC, the root cause of intestinal epithelial tumour development, may therefore compromise both Wnt pathway regulation and epithelial cell- and tissue-polarity. We are examining these APC-mediated functions using organotypic epithelial cultures to understand their involvement in preventing tumorigenesis.
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