Characterization of novel, context-dependent modulators of WNT signaling in cancer

Abstract

WNTs comprise a family of secreted proteins that play critical roles in both embryogenesis and in the etiology of human diseases such as cancer. Even after more than three decades of research, our understanding of the complex roles of various WNT signaling pathways in cancer is rudimentary at best. Just as either activating or inactivating different WNT signaling pathways results in unique consequences at different stages of animal development and in different tissues types during embryogenesis, so too do WNTs contribute to cancer progression in a context-dependent manner. The work presented in this dissertation identifies and characterizes novel modulators of WNT signaling in cancer and explores possible mechanisms of action for these signaling effectors including crosstalk with other signal transduction pathways. First, I describe a novel role for AGGF1 in colorectal cancer as a chromatin-associated enhancer of beta-catenin-dependent transcription. Second, I find that the planar cell polarity protein SCRIB does not universally act as a tumor suppressor as presumed by many researchers, but rather that SCRIB can either promote or inhibit tumorigenesis in a context-dependent manner. My working hypothesis is that this switch from pro- to anti-tumorigenic function likely involves changes in the proteins associated with SCRIB such as NOS1AP, ARHGEF7 and VANGL. Finally, I characterize a novel role for a WNT5A/FZD7/RYK/AKT pathway in promoting the growth and viability of both naïve melanoma cells and melanoma cells that have acquired resistance to BRAF/MAPK pathway inhibition. With the exception of the work on AGGF1, these studies highlight context-dependent, functional roles for beta-catenin-independent WNT signaling in modulating numerous cancer cell behaviors ranging from the regulation of cell motility to the acquirement of drug resistance.