Cytoskeletal Control and Wnt Signaling-APC's Dual Contributions in Stem Cell Division and Colorectal Cancer

Simple Summary Colorectal cancer is the third leading cause of cancer death globally. As well as the adverse health implications for the individual, there are also considerable economic and social impacts associated with workplace absence and healthcare expenses. It is critical to understand the events that govern gut homeostasis to improve cancer therapies. Intestinal cells proliferate and give rise to progenitor cells that then differentiate and actively crawl up to the villus tip where they are shed off. A balance between cell division and active migration is key to epithelium renewal. Alterations in the tumour suppressor Adenomatous polyposis coli (APC) have been found in more than 85% of colorectal cancer cases. Here we offer a perspective of APC's dual roles-cytoskeletal hub and Wnt inhibitor-for their combined impact on gut epithelium maintenance and their dysfunction leading to cancer. Intestinal epithelium architecture is sustained by stem cell division. In principle, stem cells can divide symmetrically to generate two identical copies of themselves or asymmetrically to sustain tissue renewal in a balanced manner. The choice between the two helps preserve stem cell and progeny pools and is crucial for tissue homeostasis. Control of spindle orientation is a prime contributor to the specification of symmetric versus asymmetric cell division. Competition for space within the niche may be another factor limiting the stem cell pool. An integrative view of the multiple links between intracellular and extracellular signals and molecular determinants at play remains a challenge. One outstanding question is the precise molecular roles of the tumour suppressor Adenomatous polyposis coli (APC) for sustaining gut homeostasis through its respective functions as a cytoskeletal hub and a down regulator in Wnt signalling. Here, we review our current understanding of APC inherent activities and partners in order to explore novel avenues by which APC may act as a gatekeeper in colorectal cancer and as a therapeutic target.