PDGFRβ Signaling Cooperates with β-Catenin to Modulate c-Abl and Biologic Behavior of Desmoid-Type Fibromatosis

Purpose: This study sought to identify beta-catenin targets that regulate desmoid oncogenesis and determine whether external signaling pathways, particularly those inhibited by sorafenib (e.g., PDGFR beta), affect these targets to alter natural history or treatment response in patients.Experimental Design: In vitro experiments utilized primary desmoid cell lines to examine regulation of beta-catenin targets. Relevance of results was assessed in vivo using Alliance trial A091105 correlative biopsies.Results: CTNNB1 knockdown inhibited hypoxia-regulated gene expression in vitro and reduced levels of HIF1 alpha protein. ChIP-seq identified ABL1 as a beta-catenin transcriptional target that modulated HIF1 alpha and desmoid cell proliferation. Abrogation of either CTNNB1 or HIF1A inhibited desmoid cell-induced VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1 alpha protein expression and c-Abl activity while inhibiting PDGFR beta signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by PDGF-BB. Reduction in PDGFR beta and c-Abl phosphorylation was commonly observed in biopsy samples from patients after treatment with sorafenib; markers of PDGFR beta/c-Abl pathway activation in baseline samples were associated with tumor progression in patients on the placebo arm and response to sorafenib in patients receiving treatment.Conclusions: The beta-catenin transcriptional target ABL1 is necessary for proliferation and maintenance of HIF1 alpha in desmoid cells. Regulation of c-Abl activity by PDGF signaling and targeted therapies modulates desmoid cell proliferation, thereby suggesting a reason for variable biologic behavior between tumors, a mechanism for sorafenib activity in desmoids, and markers predictive of outcome in patients.