FUS-CHOP Fusion Protein Expression Coupled to p53 Deficiency Induces Liposarcoma in Mouse but Not in Human Adipose-Derived Mesenchymal Stem/Stromal Cells§

Authors

  • Rene Rodriguez,

    Corresponding author
    1. Andalusian Stem Cell Bank, Centro de Investigación Biomédica, Consejería de Salud-Universidad de Granada, Granada, Spain
    • Andalusian Stem Cell Bank, Instituto de Investigación Biomédica, Parque Tecnológico de la Salud, Avda del Conocimiento, Armilla, Granada 18100, Spain
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    • Telephone: 34-958-894-672; Fax: 34-958-894-652

  • Ruth Rubio,

    1. Andalusian Stem Cell Bank, Centro de Investigación Biomédica, Consejería de Salud-Universidad de Granada, Granada, Spain
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  • Ivan Gutierrez-Aranda,

    1. Andalusian Stem Cell Bank, Centro de Investigación Biomédica, Consejería de Salud-Universidad de Granada, Granada, Spain
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  • Gustavo J. Melen,

    1. Andalusian Stem Cell Bank, Centro de Investigación Biomédica, Consejería de Salud-Universidad de Granada, Granada, Spain
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  • Carolina Elosua,

    1. Andalusian Stem Cell Bank, Centro de Investigación Biomédica, Consejería de Salud-Universidad de Granada, Granada, Spain
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  • Javier García-Castro,

    1. Andalusian Stem Cell Bank, Centro de Investigación Biomédica, Consejería de Salud-Universidad de Granada, Granada, Spain
    2. Instituto de Salud Carlos III, Área Biología Celular y Desarrollo, Madrid, Spain
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  • Pablo Menendez

    Corresponding author
    1. Andalusian Stem Cell Bank, Centro de Investigación Biomédica, Consejería de Salud-Universidad de Granada, Granada, Spain
    • Andalusian Stem Cell Bank, Instituto de Investigación Biomédica, Parque Tecnológico de la Salud, Avda del Conocimiento, Armilla, Granada 18100, Spain
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    • Telephone: 34-958-894-672; Fax: 34-958-894-652


  • Author contributions: R. Rodriguez: designed the study, performed experiments, analyzed the data and interpreted the results, and wrote the paper; R. Rubio, I.G.-A., and G.J.M: performed experiments; C.E.: analyzed data; J.G.-C.: conceived the study and analyzed data; P.M.: conceived the study, analyzed the data and interpreted the results and wrote the paper; P.M. and R. Rodriguez: financially supported the study.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS November 23, 2010.

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. STEM CELLS 2011; 29:179–192

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