Desmoid-type fibromatosis (DTF) tumors are soft tissue tumors arising from the fibroblast populations of connective tissue resulting in locally aggressive fibromatosis. While noninvasive, chances of relapse are high. Currently FDA approved strategies for treating DTF are scarce. The Wnt-β-catenin pathway is the major driver of DTF. However, targeting this pathway could severely damage normal cellular functions. Our group has pioneered studies on the AP-1 transcription factor aka JUN driving DTF by interacting with β-catenin. Our recent studies demonstrate that JUN transcriptionally modulates the expression of a novel pro-fibrogenic molecule called CD63. CD63 is a cell surface protein that belongs to the tetraspanin family. Molecular investigations in DTF show that JUN increases CD63 expression thereby promoting cell growth and survival of primary patient derived DTF cells. Furthermore, genetic knock down of CD63 in DTF cells significantly inhibits growth both in-vitro and in animals. Using next generation sequencing and cell-based assays we show that CD63 is high in the fibroblasts of DTF patients correlating with JUN and β-catenin expression. Our studies also reveal that JUN in concert with β-catenin transcriptionally modulates CD63. Finally, we aim to use novel 3-D cell-based assays and mouse models to show that JUN, CD63 and β-catenin all work in concert to promote the fibrotic phenotype in long term assays. This proposal is aimed at the hypothesis that the JUN- β- catenin-CD63 link is essential for the onset and progression of desmoid lesions in patients. Altogether, this study focuses on key mechanisms underlying JUN regulation of CD63 in DTF and explores the promising potential of targeting CD63 as an immunotherapeutic target to treat DTF.
The proposed research aims to elucidate the molecular mechanisms underlying desmoid tumor formation (DTF) and how this impacts the reversion of fibrosis observed in DTF patients. DTF tumors arise from fibrotic connective tissue which drive the onset of aggressive fibromatosis.
Current therapeutic modalities for DTF have solely focused on tumor monitoring, surgery, chemotherapy, and a few targeted therapeutics like sorafenib, pazopanib and nirogacestat but research on their mechanisms are still underway. However, targeting key signaling pathways like the WNT signaling pathway could have significant off-target and on-target effects that could be detrimental. This proposal investigates how the AP-1 transcription factor (aka JUN) works in concert with another key transcription factor β- catenin to drive the expression of a novel profibrogenic molecule called CD63 that is significantly elevated in desmoid tumor patients. Others and we have previously shown that JUN can promote the DTF phenotype via tumor survival and proliferation. Also, we have identified a novel molecule called CD63 to be significantly elevated in the cells of primary desmoid patients. Moreover, CD63 can be efficiently targeted using monoclonal antibody therapy with minimal to no side effects. As such, we will evaluate how JUN along with β- catenin mechanistically drives CD63 overexpression in DTF patients, how CD63 in turn promotes aggressive fibromatosis and what would be the most effective strategy to target CD63 for fibrosis reversal after onset of DTF. We expect that this work will provide knowledge pertinent towards understanding the underlying pathological mechanisms that promote fibrosis and contribute to aggressive DTF tumors ultimately providing a new avenue to develop a promising therapeutic to block tumor progression.