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

• DOI: 10.1158/1078-0432.c.7029287
• Publication Date: 2024-01-17T08:21:17Z
• Authors: Jia Hu; Meera R. Hameed; Narasimhan P. Agaram; Karissa A. Whiting; Li-Xuan Qin; Anthony M. Villano; Rachael B. O'Connor; Julian M. Rozenberg; Sonia Cohen; Katherine Prender...; Sara Kryeziu; Richard L. White; Mitchell C. Posner; Nicholas D. Socci; Mrinal M. Gounder; Samuel Singer; Aimee M. Crago

<div>AbstractPurpose:<p>This study sought to identify β-catenin targets that regulate desmoid oncogenesis and determine whether external signaling pathways, particularly those inhibited by sorafenib (e.g., PDGFRβ), affect these targets to alter natural history or treatment response in patients.</p>Experimental Design:<p><i>In vitro</i> experiments utilized primary desmoid cell lines to examine regulation of β-catenin targets. Relevance of results was assessed <i>in vivo</i> using Alliance trial A091105 correlative biopsies.</p>Results:<p><i>CTNNB1</i> knockdown inhibited hypoxia-regulated gene expression <i>in vitro</i> and reduced levels of HIF1α protein. ChIP-seq identified <i>ABL1</i> as a β-catenin transcriptional target that modulated HIF1α and desmoid cell proliferation. Abrogation of either <i>CTNNB1</i> or <i>HIF1A</i> inhibited desmoid cell–induced VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1α protein expression and c-Abl activity while inhibiting PDGFRβ signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by PDGF-BB. Reduction in PDGFRβ and c-Abl phosphorylation was commonly observed in biopsy samples from patients after treatment with sorafenib; markers of PDGFRβ/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.</p>Conclusions:<p>The β-catenin transcriptional target <i>ABL1</i> is necessary for proliferation and maintenance of HIF1α 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.</p></div>