Orthoxenografts of Testicular Germ Cell Tumors Demonstrate Genomic Changes Associated with Cisplatin Resistance and Identify PDMP as a Resensitizing Agent
Por:
Piulats, JM, Vidal, A, Garcia-Rodriguez, FJ, Munoz, C, Nadal, M, Moutinho, C, Martinez-Iniesta, M, Mora, J, Figueras, A, Guino, E, Padulles, L, Aytes, A, Mollevi, DG, Puertas, S, Martinez-Fernandez, C, Castillo, W, Juliachs, M, Moreno, V, Munoz, P, Stefanovic, M, Pujana, MA, Condom, E, Esteller, M, Germa, JR, Capella, G, Farre, L, Morales, A, Vinals, F, Garcia-del-Muro, X, Ceron, J, Villanueva, A
Publicada:
1 ago 2018
Resumen:
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. (C) 2018 AACR.
Filiaciones:
Piulats, JM:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Catalan Inst Oncol IDIBELL, Dept Med Oncol, Barcelona, Spain
Vidal, A:
Hosp Univ Bellvitge IDIBELL, CIBERONC, Dept Pathol, Barcelona, Spain
Xenopat SL, Bellvitge Hlth Sci Campus, Barcelona, Spain
Garcia-Rodriguez, FJ:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Genes Dis & Therapy Program IDIBELL, Modelling Human Dis Celegans, Barcelona, Spain
Munoz, C:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Nadal, M:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Moutinho, C:
Catalan Inst Oncol IDIBELL, Canc Epigenet & Cell Biol Program PEBC, Barcelona, Spain
Martinez-Iniesta, M:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Mora, J:
Hosp Santa Creu & Sant Pau, Dept Biochem, Barcelona, Spain
Figueras, A:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Guino, E:
Catalan Inst Oncol IDIBELL, Bioinformat Unit, Barcelona, Spain
Padulles, L:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Aytes, A:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Mollevi, DG:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Puertas, S:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Martinez-Fernandez, C:
Genes Dis & Therapy Program IDIBELL, Modelling Human Dis Celegans, Barcelona, Spain
Castillo, W:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Juliachs, M:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Moreno, V:
Catalan Inst Oncol IDIBELL, Bioinformat Unit, Barcelona, Spain
Munoz, P:
Catalan Inst Oncol IDIBELL, Canc Epigenet & Cell Biol Program PEBC, Barcelona, Spain
Stefanovic, M:
CSIC, IDIBAPS, IIBB, Dept Cell Death & Proliferat, Barcelona, Catalonia, Spain
Pujana, MA:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Condom, E:
Hosp Univ Bellvitge IDIBELL, CIBERONC, Dept Pathol, Barcelona, Spain
Esteller, M:
Catalan Inst Oncol IDIBELL, Canc Epigenet & Cell Biol Program PEBC, Barcelona, Spain
Germa, JR:
Catalan Inst Oncol IDIBELL, Dept Med Oncol, Barcelona, Spain
Capella, G:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Farre, L:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Oswaldo Cruz Fdn CPQGM FIOCRUZ, Goncalo Moniz Res Ctr, Lab Expt Pathol LAPEX, Salvador, BA, Brazil
Inst Sci & Technol Trop Dis INCT DT, Salvador, BA, Brazil
Morales, A:
Catalan Inst Oncol IDIBELL, Bioinformat Unit, Barcelona, Spain
Vinals, F:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Univ Barcelona, Dept Ciencies Fisiol 2, Barcelona, Spain
Garcia-del-Muro, X:
Catalan Inst Oncol IDIBELL, Dept Med Oncol, Barcelona, Spain
Ceron, J:
Genes Dis & Therapy Program IDIBELL, Modelling Human Dis Celegans, Barcelona, Spain
IDIBLL, Celegans Core Facilty, Barcelona, Spain
Villanueva, A:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Oncobell Program, Barcelona, Catalonia, Spain
Xenopat SL, Bellvitge Hlth Sci Campus, Barcelona, Spain
IDIBLL, Celegans Core Facilty, Barcelona, Spain
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