The molecular role of fusion oncoproteins in myxoid liposarcoma

Abstract

Myxoid liposarcoma is a rare type of tumor characterized by fusion oncogenes, most commonly FUS::DDIT3. The FUS::DDIT3 oncoprotein retains functional properties of both parental proteins, enabling it to act as an aberrant transcription factor that disrupts epigenetic and transcriptional regulation, thereby promoting tumor development. However, the precise mechanism of the fusion oncoprotein remains to be defined. The aim of this thesis was to determine the molecular role of FUS::DDIT3 in myxoid liposarcoma by studying epigenetic and transcriptional effects caused by FUS::DDIT3 expression, primarily using multi-omics approaches. We found that FUS::DDIT3, like the normal DDIT3 protein, can bind promoter regions containing binding sites of transcription factors known to dimerize with DDIT3. We further discovered that FUS::DDIT3 interacts with some of these transcription factors, together affecting downstream gene expression. Furthermore, we found that FUS::DDIT3, in contrast to DDIT3, prefers binding at distal intergenic sites enriched in the repetitive GGAAT sequence. The binding of FUS::DDIT3 to these regions may play a role in the transcriptional reprogramming specific to myxoid liposarcoma. Moreover, we show that FUS::DDIT3 interacts with and affects the SWI/SNF complex, a chromatin remodeling complex controlling epigenetic regulation. The action of FUS::DDIT3 further results in extensive downstream transcriptional regulation, enabling the single oncoprotein to disrupt normal cellular functions, such as proliferation, migration and differentiation. Here, JAK-STAT signaling plays an important role in regulating cancer stem cell properties, linked to tumor heterogeneity and chemotherapy resistance. We showed that FUS::DDIT3 upregulates phosphorylated STAT3 and that both transcription factors co-localize on chromatin to regulate a shared set of genes. Another factor with great impact on tumor development, including tumor heterogeneity, is the tumor microenvironment. Therefore, we developed an experimental model system that partly mimics in vivo conditions and showed that the myxoid liposarcoma-specific microenvironment contributes to the cellular properties. Still, data showed that FUS::DDIT3 expression, more than the microenvironment, determines the myxoid liposarcoma-specific cellular phenotype. In conclusion, the results in this thesis advance our understanding of FUS::DDIT3 and its molecular functions in myxoid liposarcoma and reveal mechanisms that may represent promising therapeutic targets for targeted therapies and improved treatment outcomes.