Establishment and characterisation of testicular cancer patient-derived xenograft models for preclinical evaluation of novel therapeutic strategies

• Published in: Scientific reports 2020-11, Vol.10 (1), p.18938, Article 18938
• Main Authors: de Vries, Gerda, Rosas-Plaza, Ximena, Meersma, Gert Jan, Leeuwenburgh, Vincent C., Kok, Klaas, Suurmeijer, Albert J. H., van Vugt, Marcel A. T. M., Gietema, Jourik A., de Jong, Steven
• Format: Article
• Language: English
• Subjects: 631/67/1679; 631/67/1836; 631/67/70; Cancer; Chemoresistance; Chemotherapy; Cisplatin; Copy number; Cyclophilin A - genetics; Cyclophilin A - metabolism; DNA Copy Number Variations - genetics; Drug development; Genotype; Humanities and Social Sciences; Humans; Immunohistochemistry; Ki-67 Antigen - genetics; Ki-67 Antigen - metabolism; Male; MDM2 protein; Mechanistic Target of Rapamycin Complex 1 - genetics; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mechanistic Target of Rapamycin Complex 2 - genetics; Mechanistic Target of Rapamycin Complex 2 - metabolism; multidisciplinary; Mutation - genetics; Neoplasms, Germ Cell and Embryonal - genetics; Neoplasms, Germ Cell and Embryonal - metabolism; p53 Protein; Patients; Polymorphism, Single Nucleotide - genetics; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Sequence Analysis, RNA - methods; Solid tumors; Teratoma; Testes; Testicular cancer; Testicular Neoplasms - genetics; Testicular Neoplasms - metabolism; Tumors; Whole Exome Sequencing - methods; Xenografts; Yolk; Yolk sac
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-75518-3

Testicular cancer (TC) is the most common solid tumour in young men. While cisplatin-based chemotherapy is highly effective in TC patients, chemoresistance still accounts for 10% of disease-related deaths. Pre-clinical models that faithfully reflect patient tumours are needed to assist in target discovery and drug development. Tumour pieces from eight TC patients were subcutaneously implanted in NOD scid gamma (NSG) mice. Three patient-derived xenograft (PDX) models of TC, including one chemoresistant model, were established containing yolk sac tumour and teratoma components. PDX models and corresponding patient tumours were characterised by H&E, Ki-67 and cyclophilin A immunohistochemistry, showing retention of histological subtypes over several passages. Whole-exome sequencing, copy number variation analysis and RNA-sequencing was performed on these TP53 wild type PDX tumours to assess the effects of passaging, showing high concordance of molecular features between passages. Cisplatin sensitivity of PDX models corresponded with patients’ response to cisplatin-based chemotherapy. MDM2 and mTORC1/2 targeted drugs showed efficacy in the cisplatin sensitive PDX models. In conclusion, we describe three PDX models faithfully reflecting chemosensitivity of TC patients. These models can be used for mechanistic studies and pre-clinical validation of novel therapeutic strategies in testicular cancer.