title: FUS-CHOP fusion protein expression coupled to p53 deficiency induces liposarcoma in mouse but not in human adipose-derived mesenchymal stem/stromal cells.
abstract: Human sarcomas have been modeled in mice by expression of specific fusion genes in mesenchymal stem cells (MSCs). However, sarcoma models based on human MSCs are still missing. We attempted to develop a model of liposarcoma by expressing FUS (FUsed in Sarcoma; also termed TLS, Translocated in LipoSarcoma)-CHOP (C/EBP HOmologous Protein; also termed DDIT3, DNA Damage-Inducible Transcript 3), a hallmark mixoid liposarcoma-associated fusion oncogene, in wild-type and p53-deficient mouse and human adipose-derived mesenchymal stem/stromal cells (ASCs). FUS-CHOP induced liposarcoma-like tumors when expressed in p53(-/-) but not in wild-type (wt) mouse ASCs (mASCs). In the absence of FUS-CHOP, p53(-/-) mASCs forms leiomyosarcoma, indicating that the expression of FUS-CHOP redirects the tumor genesis/phenotype. FUS-CHOP expression in wt mASCs does not initiate sarcomagenesis, indicating that p53 deficiency is required to induce FUS-CHOP-mediated liposarcoma in fat-derived mASCs. In a human setting, p53-deficient human ASCs (hASCs) displayed a higher in vitro growth rate and a more extended lifespan than wt hASCs. However, FUS-CHOP expression did not induce further changes in culture homeostasis nor initiated liposarcoma in either wt or p53-depleted hASCs. These results indicate that FUS-CHOP expression in a p53-deficient background is sufficient to initiate liposarcoma in mouse but not in hASCs, suggesting the need of additional cooperating mutations in hASCs. A microarray gene expression profiling has shed light into the potential deregulated pathways in liposarcoma formation from p53-deficient mASCs expressing FUS-CHOP, which might also function as potential cooperating mutations in the transformation process from hASCs.
authors: Andalusian Stem Cell Bank, Centro de Investigación Biomédica, Consejería de Salud-Universidad de Granada, Granada, Spain. rene.rodriguez@juntadeandalucia.es
authors: Rene
authors: R
authors: Rodriguez
authors: Ruth
authors: R
authors: Rubio
authors: Ivan
authors: I
authors: Gutierrez-Aranda
authors: Gustavo J
authors: GJ
authors: Melen
authors: Carolina
authors: C
authors: Elosua
authors: Javier
authors: J
authors: García-Castro
authors: Pablo
authors: P
authors: Menendez
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D008080:Liposarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics
chemical_list: C497249:DDIT3 protein, human; D034702:RNA-Binding Protein FUS; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D051742:Transcription Factor CHOP