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.
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References
Sandberg AA . Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: liposarcoma. Cancer Genet Cytogenet 2004; 155: 1–24.
World Health Organisation Classification of Tumors Pathology and genetics of tumors of soft tissue and bone. IARC Press, Lyon, France, 2002.
Demicco EG, Torres KE, Ghadimi MP, Colombo C, Bolshakov S, Hoffman A et al. Involvement of the PI3K/Akt pathway in myxoid/round cell liposarcoma. Mod Pathol 2012; 25: 212–221.
Barretina J, Taylor BS, Banerji S, Ramos AH, Lagos-Quintana M, Decarolis PL et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat Genet 2010; 42: 715–721.
Negri T, Virdis E, Brich S, Bozzi F, Tamborini E, Tarantino E et al. Functional mapping of receptor tyrosine kinases in myxoid liposarcoma. Clin Cancer Res 2010; 16: 3581–3593.
Crozat A, Aman P, Mandahl N, Ron D . Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 1993; 363: 640–644.
Rabbitts TH, Forster A, Larson R, Nathan P . Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma. Nat Genet 1993; 4: 175–180.
Prasad DD, Ouchida M, Lee L, Rao VN, Reddy ES . TLS/FUS fusion domain of TLS/FUS-erg chimeric protein resulting from the t(16;21) chromosomal translocation in human myeloid leukemia functions as a transcriptional activation domain. Oncogene 1994; 9: 3717–3729.
Sanchez-Garcia I, Rabbitts TH . Transcriptional activation by TAL1 and FUS-CHOP proteins expressed in acute malignancies as a result of chromosomal abnormalities. Proc Natl Acad Sci USA 1994; 91: 7869–7873.
Ron D, Habener JF . CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes Dev 1992; 6: 439–453.
Goransson M, Wedin M, Aman P . Temperature-dependent localization of TLS-CHOP to splicing factor compartments. Exp Cell Res 2002; 278: 125–132.
Ramji DP, Foka P . CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem J 2002; 365: 561–575.
Batchvarova N, Wang XZ, Ron D . Inhibition of adipogenesis by the stress-induced protein CHOP (Gadd153). EMBO J 1995; 14: 4654–4661.
Kuroda M, Ishida T, Takanashi M, Satoh M, Machinami R, Watanabe T . Oncogenic transformation and inhibition of adipocytic conversion of preadipocytes by TLS/FUS-CHOP type II chimeric protein. Am J Pathol 1997; 151: 735–744.
Adelmant G, Gilbert JD, Freytag SO . Human translocation liposarcoma-CCAAT/enhancer binding protein (C/EBP) homologous protein (TLS-CHOP) oncoprotein prevents adipocyte differentiation by directly interfering with C/EBPbeta function. J Biol Chem 1998; 273: 15574–15581.
Perez-Mancera PA, Bermejo-Rodriguez C, Sanchez-Martin M, Abollo-Jimenez F, Pintado B, Sanchez-Garcia I . FUS-DDIT3 prevents the development of adipocytic precursors in liposarcoma by repressing PPARgamma and C/EBPalpha and activating eIF4E. PLoS ONE 2008; 3: e2569.
Perez-Losada J, Pintado B, Gutierrez-Adan A, Flores T, Banares-Gonzalez B, del Campo JC et al. The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice. Oncogene 2000; 19: 2413–2422.
Riggi N, Cironi L, Provero P, Suva ML, Stehle JC, Baumer K et al. Expression of the FUS-CHOP fusion protein in primary mesenchymal progenitor cells gives rise to a model of myxoid liposarcoma. Cancer Res 2006; 66: 7016–7023.
Graadt van Roggen JF, Hogendoorn PC, Fletcher CD . Myxoid tumours of soft tissue. Histopathology 1999; 35: 291–312.
Antonescu CR, Tschernyavsky SJ, Decuseara R, Leung DH, Woodruff JM, Brennan MF et al. Prognostic impact of P53 status, TLS-CHOP fusion transcript structure, and histological grade in myxoid liposarcoma: a molecular and clinicopathologic study of 82 cases. Clin Cancer Res 2001; 7: 3977–3987.
Knight JC, Renwick PJ, Dal Cin P, Van den Berghe H, Fletcher CD . Translocation t(12;16)(q13;p11) in myxoid liposarcoma and round cell liposarcoma: molecular and cytogenetic analysis. Cancer Res 1995; 55: 24–27.
Panagopoulos I, Mandahl N, Ron D, Hoglund M, Nilbert M, Mertens F et al. Characterization of the CHOP breakpoints and fusion transcripts in myxoid liposarcomas with the 12;16 translocation. Cancer Res 1994; 54: 6500–6503.
Powers MP, Wang WL, Hernandez VS, Patel KS, Lev DC, Lazar AJ et al. Detection of myxoid liposarcoma-associated FUS-DDIT3 rearrangement variants including a newly identified breakpoint using an optimized RT-PCR assay. Mod Pathol 2010; 23: 1307–1315.
Bode-Lesniewska B, Frigerio S, Exner U, Abdou MT, Moch H, Zimmermann DR . Relevance of translocation type in myxoid liposarcoma and identification of a novel EWSR1-DDIT3 fusion. Genes Chromosomes Cancer 2007; 46: 961–971.
Gajate C, An F, Mollinedo F . Differential cytostatic and apoptotic effects of ecteinascidin-743 in cancer cells. Transcription-dependent cell cycle arrest and transcription-independent JNK and mitochondrial mediated apoptosis. J Biol Chem 2002; 277: 41580–41589.
Izbicka E, Lawrence R, Raymond E, Eckhardt G, Faircloth G, Jimeno J et al. In vitro antitumor activity of the novel marine agent, ecteinascidin-743 (ET-743, NSC-648766) against human tumors explanted from patients. Ann Oncol 1998; 9: 981–987.
Li WW, Takahashi N, Jhanwar S, Cordon-Cardo C, Elisseyeff Y, Jimeno J et al. Sensitivity of soft tissue sarcoma cell lines to chemotherapeutic agents: identification of ecteinascidin-743 as a potent cytotoxic agent. Clin Cancer Res 2001; 7: 2908–2911.
Hendriks HR, Fiebig HH, Giavazzi R, Langdon SP, Jimeno JM, Faircloth GT . High antitumour activity of ET743 against human tumour xenografts from melanoma, non-small-cell lung and ovarian cancer. Ann Oncol 1999; 10: 1233–1240.
Erba E, Bergamaschi D, Bassano L, Damia G, Ronzoni S, Faircloth GT et al. Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action. Eur J Cancer 2001; 37: 97–105.
Valoti G, Nicoletti MI, Pellegrino A, Jimeno J, Hendriks H, D'Incalci M et al. Ecteinascidin-743, a new marine natural product with potent antitumor activity on human ovarian carcinoma xenografts. Clin Cancer Res 1998; 4: 1977–1983.
D'Incalci M, Jimeno J . Preclinical and clinical results with the natural marine product ET-743. Expert Opin Investig Drugs 2003; 12: 1843–1853.
Zewail-Foote M, Hurley LH . Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove. J Med Chem 1999; 42: 2493–2497.
D'Incalci M, Galmarini CM . A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther 2010; 9: 2157–2163.
Damia G, Imperatori L, Stefanini M, D'Incalci M . Sensitivity of CHO mutant cell lines with specific defects in nucleotide excision repair to different anti-cancer agents. Int J Cancer 1996; 66: 779–783.
Takebayashi Y, Pourquier P, Zimonjic DB, Nakayama K, Emmert S, Ueda T et al. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med 2001; 7: 961–966.
Tavecchio M, Simone M, Erba E, Chiolo I, Liberi G, Foiani M et al. Role of homologous recombination in trabectedin-induced DNA damage. Eur J Cancer 2008; 44: 609–618.
Minuzzo M, Marchini S, Broggini M, Faircloth G, D'Incalci M, Mantovani R . Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. Proc Natl Acad Sci USA 2000; 97: 6780–6784.
Jin S, Gorfajn B, Faircloth G, Scotto KW . Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation. Proc Natl Acad Sci USA 2000; 97: 6775–6779.
Friedman D, Hu Z, Kolb EA, Gorfajn B, Scotto KW . Ecteinascidin-743 inhibits activated but not constitutive transcription. Cancer Res 2002; 62: 3377–3381.
Bonfanti M, La Valle E, Fernandez Sousa Faro JM, Faircloth G, Caretti G, Mantovani R et al. Effect of ecteinascidin-743 on the interaction between DNA binding proteins and DNA. Anticancer Drug Des 1999; 14: 179–186.
Minuzzo M, Ceribelli M, Pitarque-Marti M, Borrelli S, Erba E, DiSilvio A et al. Selective effects of the anticancer drug Yondelis (ET-743) on cell-cycle promoters. Mol Pharmacol 2005; 68: 1496–1503.
Germano G, Frapolli R, Simone M, Tavecchio M, Erba E, Pesce S et al. Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res 2010; 70: 2235–2244.
Germano G, Frapolli R, Belgiovine C, Anselmo A, Pesce S, Liguori M et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 2013; 23: 249–262.
Grosso F, Jones RL, Demetri GD, Judson IR, Blay JY, Le Cesne A et al. Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Lancet Oncol 2007; 8: 595–602.
Grosso F, Sanfilippo R, Virdis E, Piovesan C, Collini P, Dileo P et al. Trabectedin in myxoid liposarcomas (MLS): a long-term analysis of a single-institution series. Ann Oncol 2009; 20: 1439–1444.
Charytonowicz E, Terry M, Coakley K, Telis L, Remotti F, Cordon-Cardo C et al. PPARgamma agonists enhance ET-743-induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma. J Clin Invest 2012; 122: 886–898.
Forni C, Minuzzo M, Virdis E, Tamborini E, Simone M, Tavecchio M et al. Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors. Mol Cancer Ther 2009; 8: 449–457.
Frapolli R, Tamborini E, Virdis E, Bello E, Tarantino E, Marchini S et al. Novel models of myxoid liposarcoma xenografts mimicking the biological and pharmacologic features of human tumors. Clin Cancer Res 2010; 16: 4958–4967.
Gronchi A, Bui BN, Bonvalot S, Pilotti S, Ferrari S, Hohenberger P et al. Phase II clinical trial of neoadjuvant trabectedin in patients with advanced localized myxoid liposarcoma. Ann Oncol 2012; 23: 771–776.
Hurley LH . DNA and its associated processes as targets for cancer therapy. Nat Rev Cancer 2002; 2: 188–200.
Broggini M, D'Incalci M . Modulation of transcription factor—DNA interactions by anticancer drugs. Anticancer Drug Des 1994; 9: 373–387.
Dervan PB, Burli RW . Sequence-specific DNA recognition by polyamides. Curr Opin Chem Biol 1999; 3: 688–693.
Broggini M, Coley HM, Mongelli N, Pesenti E, Wyatt MD, Hartley JA et al. DNA sequence-specific adenine alkylation by the novel antitumor drug tallimustine (FCE 24517), a benzoyl nitrogen mustard derivative of distamycin. Nucleic Acids Res 1995; 23: 81–87.
Chiang SY, Welch J, Rauscher FJ 3rd, Beerman TA . Effects of minor groove binding drugs on the interaction of TATA box binding protein and TFIIA with DNA. Biochemistry 1994; 33: 7033–7040.
Pommier Y, Kohlhagen G, Bailly C, Waring M, Mazumder A, Kohn KW . DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata. Biochemistry 1996; 35: 13303–13309.
Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM . Transcriptional regulation of adipogenesis. Genes Dev 2000; 14: 1293–1307.
Rosen ED, MacDougald OA . Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 2006; 7: 885–896.
Yeh WC, Cao Z, Classon M, McKnight SL . Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes Dev 1995; 9: 168–181.
Wang WL, Katz D, Araujo DM, Ravi V, Ludwig JA, Trent JC et al. Extensive adipocytic maturation can be seen in myxoid liposarcomas treated with neoadjuvant doxorubicin and ifosfamide and pre-operative radiation therapy. Clin Sarcoma Res 2012; 2: 25.
Licitra L, Perrone F, Bossi P, Suardi S, Mariani L, Artusi R et al. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 2006; 24: 5630–5636.
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The study was supported by two AIRC grants to MD and SP.
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Dr MD has received compensation for a scientific advisory board of PharmaMar. Dr CMG and Dr JMFS-F are employees and shareholders of PharmaMar. PGC has received compensation for consultancies, speaker fees and travel expenses for medical meetings from PharmaMar. The remaining authors declare no conflict of interest.
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Di Giandomenico, S., Frapolli, R., Bello, E. et al. Mode of action of trabectedin in myxoid liposarcomas. Oncogene 33, 5201–5210 (2014). https://doi.org/10.1038/onc.2013.462
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DOI: https://doi.org/10.1038/onc.2013.462
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