Mode of action of trabectedin in myxoid liposarcomas

S. Di Giandomenico, R. Frapolli, E. Bello, S. Uboldi, S. A. Licandro, S. Marchini, L. Beltrame, S. Brich, V. Mauro, E. Tamborini, S. Pilotti, P. G. Casali, F. Grosso, R. Sanfilippo, A. Gronchi, R. Mantovani, R. Gatta, C. M. Galmarini, J. M F Sousa-Faro, M. D'Incalci

Research output: Contribution to journalArticle

78 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5201-5210
Number of pages10
JournalOncogene
Volume33
Issue number44
DOIs
Publication statusPublished - Oct 30 2014

Fingerprint

trabectedin
Myxoid Liposarcoma
Liposarcoma
Chromatin Immunoprecipitation
Gene Fusion
Cellular Structures
Fibronectins
Heterografts
Doxorubicin
Blood Vessels
Western Blotting

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Mode of action of trabectedin in myxoid liposarcomas. / Di Giandomenico, S.; Frapolli, R.; Bello, E.; Uboldi, S.; Licandro, S. A.; Marchini, S.; Beltrame, L.; Brich, S.; Mauro, V.; Tamborini, E.; Pilotti, S.; Casali, P. G.; Grosso, F.; Sanfilippo, R.; Gronchi, A.; Mantovani, R.; Gatta, R.; Galmarini, C. M.; Sousa-Faro, J. M F; D'Incalci, M.

In: Oncogene, Vol. 33, No. 44, 30.10.2014, p. 5201-5210.

Research output: Contribution to journalArticle

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, JMF & D'Incalci, M 2014, 'Mode of action of trabectedin in myxoid liposarcomas', Oncogene, vol. 33, no. 44, pp. 5201-5210. https://doi.org/10.1038/onc.2013.462
Di Giandomenico S, Frapolli R, Bello E, Uboldi S, Licandro SA, Marchini S et al. Mode of action of trabectedin in myxoid liposarcomas. Oncogene. 2014 Oct 30;33(44):5201-5210. https://doi.org/10.1038/onc.2013.462
Di Giandomenico, S. ; Frapolli, R. ; Bello, E. ; Uboldi, S. ; Licandro, S. A. ; Marchini, S. ; Beltrame, L. ; Brich, S. ; Mauro, V. ; Tamborini, E. ; Pilotti, S. ; Casali, P. G. ; Grosso, F. ; Sanfilippo, R. ; Gronchi, A. ; Mantovani, R. ; Gatta, R. ; Galmarini, C. M. ; Sousa-Faro, J. M F ; D'Incalci, M. / Mode of action of trabectedin in myxoid liposarcomas. In: Oncogene. 2014 ; Vol. 33, No. 44. pp. 5201-5210.
@article{9d733b747d654c28b9c8f5cdcf3f6b66,
title = "Mode of action of trabectedin in myxoid liposarcomas",
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.",
author = "{Di Giandomenico}, S. and R. Frapolli and E. Bello and S. Uboldi and Licandro, {S. A.} and S. Marchini and L. Beltrame and S. Brich and V. Mauro and E. Tamborini and S. Pilotti and Casali, {P. G.} and F. Grosso and R. Sanfilippo and A. Gronchi and R. Mantovani and R. Gatta and Galmarini, {C. M.} and Sousa-Faro, {J. M F} and M. D'Incalci",
year = "2014",
month = "10",
day = "30",
doi = "10.1038/onc.2013.462",
language = "English",
volume = "33",
pages = "5201--5210",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "44",

}

TY - JOUR

T1 - Mode of action of trabectedin in myxoid liposarcomas

AU - Di Giandomenico, S.

AU - Frapolli, R.

AU - Bello, E.

AU - Uboldi, S.

AU - Licandro, S. A.

AU - Marchini, S.

AU - Beltrame, L.

AU - Brich, S.

AU - Mauro, V.

AU - Tamborini, E.

AU - Pilotti, S.

AU - Casali, P. G.

AU - Grosso, F.

AU - Sanfilippo, R.

AU - Gronchi, A.

AU - Mantovani, R.

AU - Gatta, R.

AU - Galmarini, C. M.

AU - Sousa-Faro, J. M F

AU - D'Incalci, M.

PY - 2014/10/30

Y1 - 2014/10/30

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84920265709&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84920265709&partnerID=8YFLogxK

U2 - 10.1038/onc.2013.462

DO - 10.1038/onc.2013.462

M3 - Article

VL - 33

SP - 5201

EP - 5210

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 44

ER -