Abstract 1894: Canonical Wnt-associated extracellular matrix in adrenocortical carcinoma

Abstract

Abstract Adrenocortical carcinoma (ACC) is a rare and often aggressive cancer that affects 1-2 people per million in the United States annually. Genomic alterations activating canonical Wnt signaling occur in approximately 40% of ACCs and are associated with poor prognosis. However, the biological consequences of constitutive canonical Wnt activation in ACC are poorly understood. To better characterize the transcriptional programs that are engaged in ACC, we performed independent component analysis on The Cancer Genome Atlas (TCGA) ACC transcriptome dataset to identify components of coordinately expressed genes. One of the components identified was significantly enriched for Wnt signaling (p = 0.001) and was strongly associated with somatic CTNNB1 (β-catenin) mutations (p = 2.276e-07). Interestingly, this Wnt-enriched component also showed enrichment for extracellular matrix (ECM)-receptor interaction (p = 0.00139), including (but not restricted to) expression of COL11A1 (Collagen alpha-1(XI)), LAMC3 (Laminin, gamma 3), and ITGA2 (Integrin, alpha 2), suggesting that Wnt signaling is regulating cell-ECM interactions and ECM composition in ACC. To follow up on this observation, we performed immunohistochemical staining on tissue microarrays (TMAs) containing 97 ACC samples. We observed a strong correlation of COL11A1 expression and nuclear β-catenin localization (p = 0.0088), suggesting COL11A1 expression may be regulated by canonical Wnt signaling. Furthermore, COL11A1 expression was associated with decreased overall survival (p = 0.0003) and decreased event-free survival (p = 0.0075). To determine whether ECM and ECM-receptor genes are regulated by canonical Wnt activity, the NCI-H295R human ACC cell line, harboring an activating CTNNB1 mutation, was used. Cells were treated with PKF115-584, an inhibitor of canonical Wnt signaling that disrupts β-catenin interaction with TCF/LEF transcription factors. PKF115-584 treatment significantly reduced expression of COL11A1, LAMC3, and ITGA2 in NCI-H295R cells at early timepoints (p≤0.05), consistent with our hypothesis that canonical Wnt signaling regulates expression of ECM components in ACC. At late timepoints following PKF115-584 treatment, NCI-H295R cell viability decreased, indicating that canonical Wnt activity may regulate cell survival in ACC. These results illustrate a novel role for canonical Wnt activity in ACC, and suggest that β-catenin-regulated transcription of ECM and ECM-receptor components may promote cancer cell survival and aggressive disease. Future studies are aimed at characterizing the contribution of extracellular proteins to ACC phenotypes. Citation Format: Morgan K. Penny, Antonio M. Lerario, Chris LaPensee, Thomas J. Giordano, Gary D. Hammer. Canonical Wnt-associated extracellular matrix in adrenocortical carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1894.