73 Understanding the Role of Noncanonical Wnt Signaling Adrenal Biology and Cancer

Faculty Mentor: Kaitlin Basham (Oncological Sciences, University of Utah)

The Wnt signaling pathway plays an important role in development and homeostasis andis aberrantly activated in many human cancers. There are two main Wnt pathways: the canonicalWnt pathway, involving regulation of b-catenin; and the noncanonical Wnt pathway, whichmediates signaling through other effector molecules. One tissue where Wnt signaling is criticalfor growth and maintenance is the adrenal gland. In cases of adrenocortical carcinoma (ACC), anaggressive and rare cancer in the adrenal cortex, the Wnt signaling pathway is aberrantlyactivated. ZNRF3 is a negative regulator of Wnt signaling and loss-of-function mutations inZNRF3 is one of the most frequent genetic alterations in ACC. ZNRF3 promotes the turnover ofthe WNT receptor FZD, which can act together with coreceptors for both the canonical andnoncanonical pathways. Because FZD has the potential act through both pathways, ZNRF3 maybe involved in the regulation of both canonical and noncanonical Wnt signaling. To examine thenoncanonical pathway, we looked at the WNT coreceptor RYK and found that combinedconditional loss of Ryk and Znrf3 in the adrenal reduces the hyperplasia seen in mice withconditional Znrf3 loss alone. We also observed an increase in myeloid immune infiltration in 6-week female mice when both genes were absent. These results suggest that ZNRF3 interacts withRYK, influencing noncanonical Wnt signaling, and that Ryk loss in the absence of Znrf3 mayplay a role in immune infiltration in the adrenal. The finding that ZNRF3 interacts with bothcanonical and noncanonical signaling may have important implications for treatment of ACC andtargeting upstream events in the Wnt pathway.