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Clin Cancer Res. 2018 Aug 1;24(15):3755-3766. doi: 10.1158/1078-0432.CCR-17-1898. Epub 2018 Apr 4.

Orthoxenografts of Testicular Germ Cell Tumors Demonstrate Genomic Changes Associated with Cisplatin Resistance and Identify PDMP as a Resensitizing Agent.

Author information

1
Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), Oncobell Program, L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
2
Department of Medical Oncology, Catalan Institute of Oncology (IDIBELL), Barcelona, Spain.
3
Department of Pathology, Hospital Universitari de Bellvitge (IDIBELL), CIBERONC, Barcelona, Spain.
4
Xenopat S.L., Business Bioincubator, Bellvitge Health Science Campus, L'Hospitalet de Llobregat, Barcelona, Spain.
5
Modelling Human Diseases in C. elegans. Genes, Disease and Therapy Program (IDIBELL), Barcelona, Spain.
6
Cancer Epigenetics and Cell Biology Program (PEBC), Catalan Institute of Oncology (IDIBELL), Barcelona, Spain.
7
Department of Biochemistry, Hospital de Sant Pau, Barcelona, Spain.
8
Bioinformatic Unit, Catalan Institute of Oncology (IDIBELL), Barcelona, Spain.
9
Department of Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), IDIBAPS, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
10
Laboratory of Experimental Pathology (LAPEX), Gonçalo Moniz Research Center, Oswaldo Cruz Foundation (CPQGM/FIOCRUZ), Salvador, Bahia, Brazil.
11
Institute of Science and Technology of Tropical Diseases (INCT/DT), Salvador, Brazil.
12
Departament de Ciencies Fisiologiques II, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
13
Modelling Human Diseases in C. elegans. Genes, Disease and Therapy Program (IDIBELL), Barcelona, Spain. avillanueva@iconcologia.net jceron@idibell.cat.
14
C. elegans Core Facilty-IDIBELL, Barcelona, Spain.
15
Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), Oncobell Program, L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain. avillanueva@iconcologia.net jceron@idibell.cat.
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Contributed equally

Abstract

Purpose: To investigate the genetic basis of cisplatin resistance as efficacy of cisplatin-based chemotherapy in the treatment of distinct malignancies is often hampered by intrinsic or acquired drug resistance of tumor cells.Experimental Design: We produced 14 orthoxenograft transplanting human nonseminomatous testicular germ cell tumors (TGCT) in mice, keeping the primary tumor features in terms of genotype, phenotype, and sensitivity to cisplatin. Chromosomal and genetic alterations were evaluated in matched cisplatin-sensitive and their counterpart orthoxenografts that developed resistance to cisplatin in nude mice.Results: Comparative genomic hybridization analyses of four matched orthoxenografts identified recurrent chromosomal rearrangements across cisplatin-resistant tumors in three of them, showing gains at 9q32-q33.1 region. We found a clinical correlation between the presence of 9q32-q33.1 gains in cisplatin-refractory patients and poorer overall survival (OS) in metastatic germ cell tumors. We studied the expression profile of the 60 genes located at that genomic region. POLE3 and AKNA were the only two genes deregulated in resistant tumors harboring the 9q32-q33.1 gain. Moreover, other four genes (GCS, ZNF883, CTR1, and FLJ31713) were deregulated in all five resistant tumors independently of the 9q32-q33.1 amplification. RT-PCRs in tumors and functional analyses in Caenorhabditis elegans (C. elegans) indicate that the influence of 9q32-q33.1 genes in cisplatin resistance can be driven by either up- or downregulation. We focused on glucosylceramide synthase (GCS) to demonstrate that the GCS inhibitor DL-threo-PDMP resensitizes cisplatin-resistant germline-derived orthoxenografts to cisplatin.Conclusions: Orthoxenografts can be used preclinically not only to test the efficiency of drugs but also to identify prognosis markers and gene alterations acting as drivers of the acquired cisplatin resistance. Clin Cancer Res; 24(15); 3755-66. ©2018 AACR.

PMID:
29618620
DOI:
10.1158/1078-0432.CCR-17-1898
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