Martin-Broto, J. | Search bioRxiv

bioRxiv2025

NAB2-STAT6 Fusion Proteins Drive Nuclear Condensate Formation and Transcriptional Reprogramming in Solitary Fibrous Tumors

Solitary fibrous tumor (SFT) is a rare and aggressive sarcoma driven by NAB2-STAT6 gene fusions, yet effective targeted therapies remain unavailable. Here, we report that the NAB2ex4-STAT6ex2 fusion variant forms nuclear condensates via liquid-liquid phase separation (LLPS) in engineered fibroblast models and primary SFT cells. These condensates co-localize with BRD4S and EGR1, key transcriptional regulators, and are functionally active, driving widespread transcriptional reprogramming. Treatment with Mithramycin A, a compound that disrupts EGR1-DNA interactions, dissolves NAB2-STAT6 condensates and reverses their aberrant gene expression and chromatin binding signatures. Our findings uncover a previously unrecognized role for NAB2-STAT6 in condensate-mediated oncogenic signaling and provide a mechanistic rationale for condensate-targeted therapy in SFT.

cancer biology↗

bioRxiv2025

Identification of BET Inhibitors (BETi) Against Solitary Fibrous Tumor (SFT) Through High-Throughput Screening (HTS)

Cancers, especially fusion oncoprotein (FO)-driven hematological cancers and sarcomas, often develop from a low number of key mutations. Solitary Fibrous Tumor (SFT) is a rare mesenchymal tumor driven by the NAB2-STAT6 oncofusion gene. Currently, the treatment options for SFT remain limited, with anti-angiogenic drugs providing only partial responses and an average survival of two years. To address this challenge, we constructed SFT cell models harboring specific NAB2-STAT6 fusion transcripts using the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology. High-throughput drug screens demonstrated that the BET inhibitor Mivebresib can differentially reduce proliferation in SFT cell models. Subsequently, BET inhibitors Mivebresib and BMS-986158 efficiently reduced tumor growth in an SFT patient-derived xenograft (PDX) animal model. Furthermore, our data showed that NAB2-STAT6 fusions may lead to higher levels of DNA damage in SFTs. Consequently, combining BET inhibitors with PARP (Poly (ADP-ribose) polymerase) or ATR inhibitors significantly enhanced anti-proliferative effects in SFT cells. Taken together, our study established BET inhibitors Mivebresib and BMS-986158 as promising anti-SFT agents. SignificanceNew therapies are a clinical need for patients with Solitary Fibrous Tumor. We demonstrated that BET inhibitors are highly active in the preclinical setting for the treatment of this sarcoma entity.

cancer biology↗