The role of APC in cellular and tissue organisation in intestinal tumorigenesis
The tumour suppressor adenomatous polyposis coli (APC) is a multifunctional protein regulating a diverse array of effector pathways essential for cellular homeostasis. In most sporadic colon cancers, truncating mutations in APC lead to the loss of the Wnt pathway and microtubule regulatory domains. Studies have established key roles of mutant APC in malignant growth via deregulation of Wnt pathway activity. However, the consequence of the loss of the microtubule regulatory domains of APC in intestinal tumorigenesis has not been determined. In addition, it is widely believed that intestinal tumorigenesis is initiated from a stem cell, with limited studies addressing the potential for adenomas originating from non-stem cells. I hypothesise that the stem cell supporting Paneth cells act as an intrinsic organising centre for the intestinal epithelia, thereby providing a barrier for tumorigenesis. I utilise intestinal tissue and generate various genetically modified 3-dimensional organoid models to study the role of APC in malignant transformation of the intestinal epithelia. I show that APC inactivation leads to alterations in tissue morphology. Intriguingly, my results reveal a novel phenotype upon loss of APC resulting in compromised intracellular organisation that is linked to the deregulation of microtubules. Sufficiency experiments suggest that the different effector roles of APC in the intestinal epithelia are domain-specific. The generation of a novel Paneth cell specific promoter allowed me to demonstrate that the loss of APC specifically in Paneth cells does not compromise intestinal epithelial tissue morphology, a key characteristic of intestinal tumorigenesis. The results presented in here demonstrate that solely the loss of APC in a Paneth cell is not sufficient to initiate intestinal tumorigenesis, suggesting that further insults could be necessary for this non-stem cell to acquire the potential to initiate tumorigenesis. My findings indicate that APC has distinct domain-specific roles in the intestinal epithelia and reveal its novel role in regulating intracellular organisation. I conclude that there are additional consequences for APC mutational inactivation in intestinal tumorigenesis beyond deregulation of the Wnt pathway activity.
APC, colorectal cancer, Microtubules, Polarity, Wnt signalling, Paneth cells, Organoids
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