Abstract 3955: The role of the Wnt/Beta-catenin pathway in adrenocortical carcinoma

Abstract

Abstract Adrenocortical carcinoma (ACC) is an aggressive cancer that affects 1-2 people per million in the United States annually. The only option for cure is surgical resection, and the 5-year survival rate for ACC remains low at 35%. Improved understanding of this disease is needed to develop rational therapies. Genomic alterations activating Wnt/Beta-catenin signaling occur in approximately 40% of ACCs and are associated with poor prognosis. However, the biologic consequences of constitutive Wnt/Beta-catenin activation in ACC are poorly understood. Treatment with Beta-catenin inhibitors BC2059 and PKF115-584 decreases viability in the NCI-H295R ACC cell line, which harbors an activating CTNNB1 (Beta-catenin) mutation. In addition, BC2059 significantly inhibits NCI-H295R tumor growth in an orthotopic xenograft model. Our data supports the hypothesis that Wnt/Beta-catenin regulates ACC cell growth and survival. To better characterize transcriptional programs engaged by Wnt/Beta-catenin signaling in ACC, we performed independent component analysis on The Cancer Genome Atlas (TCGA) ACC transcriptome dataset to identify components of coordinately expressed genes. One component is significantly enriched for Wnt signaling activity and is strongly associated with somatic CTNNB1 (Beta-catenin) mutation. The Wnt-enriched component is also enriched for extracellular matrix (ECM)-receptor interaction, including (but not restricted to) expression of COL11A1 (Collagen alpha-1(XI)), COL26A1 (Collagen alpha-1(XXVI)), LAMC3 (Laminin, gamma 3), and ITGA2 (Integrin, alpha 2), suggesting that Wnt/Beta-catenin is regulating composition of the ACC microenvironment. Current literature supports that ACC has relatively low contribution from stromal cells, suggesting that tumor-cell-derived ECM may have substantial biologic effect in the tumor microenvironment. To follow up on these observations, we performed immunohistochemical staining on tissue microarrays containing 97 ACC samples. We observed a strong correlation of COL11A1 expression and nuclear Beta-catenin localization, suggesting COL11A1 may be regulated by Wnt/Beta-catenin. Furthermore, COL11A1 expression is significantly associated with decreased overall survival and decreased event-free survival. Cell culture studies confirm that expression of COL11A1, COL26A1, and LAMC3 is significantly reduced in NCI-H295R cells treated with PKF115-584 or BC2059, consistent with our hypothesis that Wnt/Beta-catenin regulates expression of ECM components in ACC. These results illustrate a novel role for Wnt/Beta-catenin activity in ACC, and suggest that Beta-catenin-associated expression of ECM components may contribute to cancer cell survival and disease progression. Citation Format: Morgan K. Penny, Antonio M. Lerario, Chris LaPensee, Thomas J. Giordano, Ruolan Han, Erika A. Newman, Gary D. Hammer. The role of the Wnt/Beta-catenin pathway in adrenocortical carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3955.