Carcinogenesis Advance Access published online on April 29, 2007
Carcinogenesis, doi:10.1093/carcin/bgm107
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Fat-specific FUS-DDIT3-transgenic mice establish PPAR
inactivation is required to liposarcoma development
1 Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC/ Universidad de Salamanca, Campus Unamuno, 37007-SALAMANCA (SPAIN)
2 Department of Medicine, Universidad de Salamanca
3 Servicio de Anatomía Patológica, Universidad de Salamanca
# To whom correspondence should be addressed. Phone: +34-923-238403, Fax: +34-923-294813, E-mail: isg{at}usal.es
FUS-DDIT3 is a chimeric oncogene generated by the most common chromosomal translocation t(12;16)(q13;p11) associated to liposarcomas. The application of transgenic methods and the use of primary mesenchymal progenitor cells to the study of this sarcoma-associated FUS-DDIT3 gene fusion has provided insights into their in vivo functions and suggested mechanisms by which lineage selection may be achieved. These studies indicate FUS-DDIT3 contributes to differentiation arrest acting at a point in the adipocyte differentiation process after induction of PPAR
expression. To test this idea within a living mouse, we generated mice expressing FUS-DDIT3 within aP2-positive cells, because aP2 is a downstream target of PPAR expressed at the immature adipocyte stage. Here we report that FUS-DDIT3 expression was successfully induced at the aP2 stage of differentiation both in vivo and in vitro. aP2-FUS-DDIT3 mice do not develop liposarcomas and exhibit an increase in white adipose tissue size. Consistent with in vivo data, murine embryonic fibroblasts (MEFs) obtained from aP2-FUS-DDIT3 mice not only were capable of terminal differentiation but also showed an increased capacity for adipogenesis in vitro compared with wild-type MEFs. Taken together, this study provide genetic evidence that the presence of FUS-DDIT3 in an aP2-positive cell is not enough to cause liposarcoma development and establishes PPAR inactivation is required to liposarcoma development.
Key Words: liposarcoma • solid tumors • FUS-DDIT3 • cancer target cell • uncommitted/stem cell
* These authors contributed equally to this work.
Received March 2, 2007; revised March 27, 2007; accepted April 24, 2007.
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