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

Gerda De Vries,Gert Jan Meersma,Ximena Rosas-Plaza,Albert J H Suurmeijer,Marcel A T M Van Vugt,Vincent C Leeuwenburgh,Jourik A Gietema,Klaas Kok,Steven De Jong

doi:10.1038/s41598-020-75518-3

Gerda De Vries, Gert Jan Meersma + Show 7 more

Open Access

https://doi.org/10.1038/s41598-020-75518-3

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Abstract

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.

Highlights

Testicular cancer (TC) is the most common solid tumour in young men
patient-derived xenograft (PDX) model These include losses on chromosome 4 (TC4) was established from a needle biopsy of a metastatic tumour taken from a patient with refractory disease
We describe the development of subcutaneous TC PDX models

Summary

Introduction

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 diseaserelated deaths. 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. 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. Not all TC subtypes are well represented in these cell line models, with the majority of TC cell lines representing the EC subtype To overcome these limitations, preclinical research is increasingly being performed using patientderived xenograft (PDX) models. A limited number of TC PDX models has been established and described[17,18,19,20] These TC PDX models, implanted either orthotopically or subcutaneously, were derived from either primary or metastatic tissue and represent all nonseminoma subtypes. Besides a histological assessment of tumour stability, the effects of serial passaging on the genetic and transcriptional level has not yet been determined

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