Understanding and targeting Wnt receptor complex regulation in cancer

Abstract

The adult human body is built of around 3.72 × 1013 cells. These cells display a great variation in shape, size and molecular composition, which reflects the morphology and functions of distinct tissues and organs. Adult human cells can be divided roughly in two categories: differentiated cells and stem cells. Differentiated cells are non-dividing, specialized cells that perform specific tasks within a given organ, for example enterocytes and goblet cells that mediate nutrient absorption and mucus production in the intestinal epithelial lining. The main activity of stem cells, on the other hand, is to divide and replenish tissues with new cells. By tight regulation of stem cell activities, adult tissues balance self-renewal and differentiation during tissue homeostasis and repair. Tissue homeostasis is stringently dependent on communication between stem cells and surrounding differentiated cells (stem cell niche cells) via several tightly regulated signaling pathways. A major driving force for tissue renewal is mediated by Wnt-induced signaling. The ability of this pathway to drive stemness and proliferative properties is often misused by cancer cells that frequently acquire mutations in Wnt pathway components that activate signaling and bypass the need for cell-to-cell communication. The overall aim of this thesis is to unearth novel mechanisms of Wnt signaling in tissue homeostasis and cancer development. By uncovering the novel roles of RNF43 and TRIP13 in Wnt signaling pathway, we gained a new prospective on how Wnt pathway perturbations affect adult stem cells fate. Finally, we apply our knowledge to rationally develop reagents capable of targeting Wnt hypersensitive tumors.