Abstract:
:To elucidate the mechanisms behind the high sensitivity of myxoid/round cell liposarcoma (MRCL) to trabectedin and the suggested selectivity for specific subtypes, we have developed and characterized three MRCL xenografts, namely ML017, ML015 and ML004 differing for the break point of the fusion gene FUS-CHOP, respectively of type I, II and III. FUS-CHOP binding to the promoters of some target genes such as Pentraxin 3 or Fibronectin 1, assessed by chromatin immunoprecipitation, was strongly reduced in the tumor 24 h after the first or the third weekly dose of trabectedin, indicating that the drug at therapeutic doses causes a detachment of the FUS-CHOP chimera from its target promoters as previously shown in vitro. Moreover, the higher sensitivity of MRCL types I and II appears to be related to a more prolonged block of the transactivating activity of the fusion protein. Doxorubicin did not affect the binding of FUS-CHOP to target promoters. Histologically, the response to trabectedin in ML017 and ML015 was associated with a marked depletion of non-lipogenic tumoral cells and vascular component, as well as lipidic maturation as confirmed by PPARγ2 expression in western Blot. By contrast, in ML004 no major changes either in the cellularity or in the amount of mature were found, and consistently PPARγ2 was null. In conclusion, the data support the view that the selective mechanism of action of trabectedin in MRCL is specific and related to its ability to cause a functional inactivation of the oncogenic chimera with consequent derepression of the adypocytic differentiation.
journal_name
Oncogenejournal_title
Oncogeneauthors
Di Giandomenico S,Frapolli R,Bello E,Uboldi S,Licandro SA,Marchini S,Beltrame L,Brich S,Mauro V,Tamborini E,Pilotti S,Casali PG,Grosso F,Sanfilippo R,Gronchi A,Mantovani R,Gatta R,Galmarini CM,Sousa-Faro JM,D'Incalcdoi
10.1038/onc.2013.462subject
Has Abstractpub_date
2014-10-30 00:00:00pages
5201-10issue
44eissn
0950-9232issn
1476-5594pii
onc2013462journal_volume
33pub_type
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