title: Expression of FUS-CHOP fusion protein in immortalized/transformed human mesenchymal stem cells drives mixoid liposarcoma formation.
abstract: Increasing evidence supports that mesenchymal stromal/stem cells (MSCs) may represent the target cell for sarcoma development. Although different sarcomas have been modeled in mice upon expression of fusion oncogenes in MSCs, sarcomagenesis has not been successfully modeled in human MSCs (hMSCs). We report that FUS-CHOP, a hallmark fusion gene in mixoid liposarcoma (MLS), has an instructive role in lineage commitment, and its expression in hMSC sequentially immortalized/transformed with up to five oncogenic hits (p53 and Rb deficiency, hTERT over-expression, c-myc stabilization, and H-RAS(v12) mutation) drives the formation of serially transplantable MLS. This is the first model of sarcoma based on the expression of a sarcoma-associated fusion protein in hMSC, and allowed us to unravel the differentiation processes and signaling pathways altered in the MLS-initiating cells. This study will contribute to test novel therapeutic approaches and constitutes a proof-of-concept to use hMSCs as target cell for modeling other fusion gene-associated human sarcomas.
authors.affiliation: Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain.
authors.forename: Rene
authors.initials: R
authors.lastname: Rodriguez
authors.forename: Juan
authors.initials: J
authors.lastname: Tornin
authors.forename: Carlos
authors.initials: C
authors.lastname: Suarez
authors.forename: Aurora
authors.initials: A
authors.lastname: Astudillo
authors.forename: Ruth
authors.initials: R
authors.lastname: Rubio
authors.forename: Carole
authors.initials: C
authors.lastname: Yauk
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.forename: Michael
authors.initials: M
authors.lastname: Rosu-Myles
authors.forename: Juan M
authors.initials: JM
authors.lastname: Funes
authors.forename: Chris
authors.initials: C
authors.lastname: Boshoff
authors.forename: Pablo
authors.initials: P
authors.lastname: Menendez
mesh_terms: D050156:Adipogenesis; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D002461:Cell Line, Transformed; D015870:Gene Expression; D006801:Humans; D018208:Liposarcoma, Myxoid / Q000378:metabolism* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D015514:Oncogene Proteins, Fusion; D034702:RNA-Binding Protein FUS; C106030:TLS-CHOP fusion protein, human; D051742:Transcription Factor CHOP
keywords: FUS-CHOP; Mesenchymal stromal/stem cells; Mixoid liposarcoma; Oncogenic hits; Sarcomagenesis