Abstract 993: Wnt-er is coming: WNT5A promotes a slow cycling phenotype via p53 in conditions of stress

Abstract

Abstract Resistance to targeted therapy and chemotherapy increases with age. Previously, we found that aged skin fibroblasts secrete sFRP2, which decreases ß-catenin, MITF, and APE1 in melanoma cells, and promotes invasion. Loss of APE1, a key redox effector, increased DNA damage in melanoma cells and caused the cells to become resistant to targeted therapy. Here we show that the aging tumor microenvironment drives a slow cycling phenotype in melanoma cells via WNT5A and p53. We found WNT5A expression in melanoma cells correlates with p53 expression and a higher percent of slow cycling cells. Knocking down WNT5A decreases both p53 expression and the percent of slow cycling cells. When we isolated slow cycling cells by flow cytometry, we found that they have increased WNT5A, p53, and p21 expression. Analysis of patient tumors in the TCGA data base revealed that patients with higher than average p53 expression, also express WNT5A. To determine if WNT5A and p53 may be promoting the survival of metastatic melanoma in an aged microenvironment, we examined tumors from young and aged C57/BL6 mice generated using Yumm1.7 cells. We found that tumors in aged mice have a higher percentage of cells expressing p53 and increased WNT5A expression compared to tumors in young mice. Treatment of human melanoma cells with conditioned media from aged dermal fibroblasts decreases proliferation and increases the percent of slow cycling. Inhibition of p53 re-sensitizes human melanoma cells in conditioned media from aged fibroblasts to combination BRAFi/MEKi. These data suggest, it may be these slow cycling cells driven by WNT5A and p53, which are enriched in an aging microenvironment, that are driving resistance to targeted therapy in aged patients. Citation Format: Marie R. Webster, Mitchell Fane, Amanpreet Kaur, Gretchen Alicea, Brett L. Ecker, Abibatou Ndoye, Curtis Kugel, Subhasree Basu, Alexander Valiga, Jessica L. Appleton, Maureen E. Murphy, Ashani Weeraratna. Wnt-er is coming: WNT5A promotes a slow cycling phenotype via p53 in conditions of stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 993.