Working on more than gut instinct
Interruptions in the normal state of the intestine often lead to malignant transformation. Mutations of the adenomatous polyposis coli (Apc) gene that result in its inactivation play a key role in colorectal cancer (CRC), and comprise about 80 % of cases. Although it is known that Apc suppresses tumour function by negatively regulating wingless-type MMTV integration site family (Wnt) signalling, there is still much to be learned about the functional significance of the pathways downstream of Apc. There is also a gap in knowledge about the contribution of intestinal stem cells (ISCs) to CRC. The 'Wnt signalling in colorectal carcinogenesis and intestinal homeostasis' (Wnt in the intestine) project used a mouse model to study the acute consequences of Apc loss in vivo and to identify numerous novel Wnt target genes upregulated at all stages of CRC development. However, difficulties in their testing in the mouse prompted the project team to develop a Drosophila model of CRC. Drosophila melanogaster is an excellent model organism for genetic screening. It provided great insight into the mechanisms involved in the disease, with study results highlighting many commonalities between intestinal regeneration and transformation. Experimental work with the Drosophila intestine, which bears a remarkable resemblance to the vertebrate intestine, uncovered an excellent system for identifying key downstream signalling events following Apc1 loss. In this way, project researchers were able to identify many genes and pathways that are misregulated upon Apc1 loss. Study results revealed a signalling pathway connection that mediates ISC proliferation during tissue regeneration as well as in transformation. The EU-funded project researchers were able to show that hyperactivation of SRC (for sarcoma) is enough to drive hyperproliferation of ISC and intestinal hyperplasia, and that it is required for intestinal regeneration following Apc loss. Wnt in the intestine work has opened the way to a better understanding of cellular and molecular pathways involved in intestinal homeostasis, regeneration and transformation. As such, study efforts stand to contribute to the development of targeted CRC therapies and to offer new insights into regenerative medicine.
