Targeting Oncogenic Wnt/β-Catenin Signaling in Adrenocortical Carcinoma Disrupts ECM Expression and Impairs Tumor Growth

Adrenocortical carcinoma (ACC) is a rare but highly aggressive cancer with limited treatment options and poor survival for patients advanced disease. An improved understanding of the transcriptional programs engaged in ACC will help direct rational, targeted therapies. Whereas activating mutations Wnt/β-catenin signaling are frequently observed, β-catenin-dependent targets that promote tumor progression poorly understood. To address this question, we analyzed transcriptome data identified novel Wnt/β-catenin-associated signature enriched extracellular matrix (ECM) predictive survival. This suggested an oncogenic role regulating microenvironment. We further investigated minor fibrillar collagen, collagen XI alpha 1 (COL11A1), found COL11A1 expression originates specifically from cells strongly correlated both activation patient Inhibition constitutively active human cell line, NCI-H295R, significantly reduced other ECM components decreased viability. investigate preclinical potential inhibition adrenal microenvironment, developed minimally invasive orthotopic xenograft model demonstrated newly Wnt/β-catenin:TBL1 inhibitor Tegavivint growth. Together, our support aberrantly disrupts reprogramming microenvironment reduces growth Furthermore, program can be therapeutically inhibitor. These results show promise clinical development inhibitors unveil Wnt/β-catenin-regulated transcriptome.