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

• Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

Animals; Cell Line

Tumor; Cell Proliferation; Cell-Free System; Extracellular Matrix; Gene Expression Regulation

Neoplastic; Humans; Liposarcoma

Myxoid; Mice; Oncogene Proteins

Fusion; RNA-Binding Protein FUS; Tissue Scaffolds; Tumor Microenvironment; eosin; growth arrest and DNA damage inducible protein 153; hematoxylin; HLA antigen; major histocompatibility antigen class 2; RNA binding protein FUS; FUS protein

human; FUS-DDIT3 fusion protein

human; oncogene fusion protein; RNA binding protein FUS; adipogenesis; animal cell; animal experiment; animal model; antigen presentation; Article; cell adhesion; cell culture; cell cycle; cell growth; cell infiltration; cell interaction; cell invasion; cell migration; cell proliferation; chromatin assembly and disassembly; controlled study; decellularization; down regulation; endocytosis; experimental model; extracellular matrix; female; functional enrichment analysis; gene expression; gene expression profiling; gene fusion; genetic transcription; glycolysis; histology; HT-1080 cell line; human; human cell; immune response; in vivo study; liquid chromatography-mass spectrometry; mass spectrometry; metabolism; mouse; myxosarcoma; nonhuman; nucleotide metabolism; oncogene; phenotype; protein expression; proteomics; RNA extraction; RNA sequencing; RNA synthesis; sarcoma cell; single cell RNA seq; tumor cell; tumor microenvironment; tumor xenograft; upregulation; animal; cell free system; chemistry; gene expression regulation; genetics; pathology; tumor cell line

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