PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [RNA-seq I]

The mechanisms underlying oncogenesis in desmoid-type fibromatosis are poorly understood. This project sought to understand how β-catenin may function to promote desmoid formation and how external signaling by PDGFRβ modulates this activity. To examine this question, RNA-seq was performed on CTNNB1 knock-downs. Gene set enrichment analysis suggested that the oncogene controlled HIF1 and angiogenesis pathways; expression of related genes accurately differentiated desmoids analyzed by U133A array from normal mesenchymal tissues. We identified c-ABL as a direct transcriptional target of β-catenin that promoted HIF1α expression in desmoid cells. We also noted that c-ABL activity was enhanced by PDGFRβ. PDGFRβ enhanced desmoid cell proliferation and c-ABL was necessary for desmoid proliferation. To identify potential markers of PDGFRβ/c-ABL activity in vivo, we assessed RNA-seq of desmoid cells treated with PDGF-BB. ERG1 transcription was highly upregulate and IHC of ERG1 was subsequently used to assess outcomes in desmoid patients with biopsies available for testing. 1. Primary desmoid cell line DES9525 were treated with shRNA directed against CTNNB1, selected with antibiotic and RNA-seq analyzed on both CTNNB1 knock-downs and scramble controls 2. Primary desmoid cell line DES9525 was treated with PDGF-BB (20ng/ml) for 24 hours and RNA-seq performed on both treated and untreated cells