Deciphering the role of FUS::DDIT3 expression and tumor microenvironment in myxoid liposarcoma development.

Ranji P, Jonasson E, Andersson L, Filges S, Luna Santamaría M, Vannas C, Dolatabadi S, Gustafsson A, Myklebost O, Håkansson J, Fagman H, Landberg G, Åman P, Ståhlberg A

J Transl Med 22 (1) 389 [2024-04-26; online 2024-04-26]

Myxoid liposarcoma (MLS) displays a distinctive tumor microenvironment and is characterized by the FUS::DDIT3 fusion oncogene, however, the precise functional contributions of these two elements remain enigmatic in tumor development. To study the cell-free microenvironment in MLS, we developed an experimental model system based on decellularized patient-derived xenograft tumors. We characterized the cell-free scaffold using mass spectrometry. Subsequently, scaffolds were repopulated using sarcoma cells with or without FUS::DDIT3 expression that were analyzed with histology and RNA sequencing. Characterization of cell-free MLS scaffolds revealed intact structure and a large variation of protein types remaining after decellularization. We demonstrated an optimal culture time of 3 weeks and showed that FUS::DDIT3 expression decreased cell proliferation and scaffold invasiveness. The cell-free MLS microenvironment and FUS::DDIT3 expression both induced biological processes related to cell-to-cell and cell-to-extracellular matrix interactions, as well as chromatin remodeling, immune response, and metabolism. Data indicated that FUS::DDIT3 expression more than the microenvironment determined the pre-adipocytic phenotype that is typical for MLS. Our experimental approach opens new means to study the tumor microenvironment in detail and our findings suggest that FUS::DDIT3-expressing tumor cells can create their own extracellular niche.

Clinical Genomics Gothenburg [Service]

Glycoproteomics and MS Proteomics [Service]

PubMed 38671504

DOI 10.1186/s12967-024-05211-w

Crossref 10.1186/s12967-024-05211-w

pmc: PMC11046918
pii: 10.1186/s12967-024-05211-w