PDGFRß signaling cooperates with ß-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [ChIP-seq]
Purpose: This study sought to identify signaling pathways that modulate ß-catenin function in desmoid cells, affecting natural history and sorafenib response. Experimental Design: In vitro experiments utilized primary desmoid cell lines to examine interaction of ß-catenin signaling with other pathways. Relevance of in vitro results was assessed in surgical specimens and Alliance trial A091105 correlative biopsies.  Results: CTNNB1 knockdown inhibited hypoxia-regulated gene expression in vitro and reduced levels of HIF1a. Expression of hypoxia-associated genes clustered desmoids separately from normal mesenchymal tissue. ChIP-seq identified ABL1 as a ß-catenin transcriptional target that modulated HIF1a protein expression and desmoid cell proliferation. Abrogation of either CTNNB1 or HIF1 inhibited the ability of desmoid cells to induce VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1a protein expression and c-Abl activity while inhibiting PDGFRß signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by activation of PDGF signaling. Reduction in PDGFRß and c-Abl phosphorylation was commonly observed in samples from patients after treatment with sorafenib; baseline samples in patients with greater drug response tended to have higher baseline PDGFRß/c-Abl pathway activation.  Conclusions: The ß-catenin transcriptional target ABL1 is necessary for proliferation and maintenance of HIF1a protein expression 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. Overall design: Experimental Design: In vitro experiments utilized primary desmoid cell lines to examine interaction of ß-catenin signaling with other pathways. Relevance of in vitro results was assessed in surgical specimens and Alliance trial A091105 correlative biopsies.