Development of a novel allograft model of prostate cancer: a new tool to inform clinical translation

Charles M. Haughey, Debayan Mukherjee, Rebecca E. Steele, Amy Popple, Lara Dura-Perez, Adam Pickard, Suneil Jain, Paul B. Mullan, Rich Williams, Pedro Oliveira, Niamh E. Buckley, Jamie Honeychurch, Richard Williams, Simon McDade, Timothy Illidge, Ian G. Mills, Sharon L. Eddie

Research output: Other contribution

Abstract

Background: Allograft models enable characterisation of genomic drivers and treatment responses by modelling immune and micro-environmental changes more accurately than xenografts. Despite this, few models are available to the prostate cancer (PCa) community. This study presents a novel allograft model of high-risk, localised PCa. In characterising this model we have focused on its response to radiotherapy (RT).Methods: The DVL3 cell line was derived from a transgenic trp53-/-/Pten-/- mouse model and characterised both in vitro and in vivo. The DVL3 cells were allografted and response to RT was investigated and compared to the TRAMP-C1 model. Extensive tumour profiling in the DVL3 model was performed using flow cytometry, immunohistochemistry and RNA-seq.Results: In vitro the DVL3 cells expressed basal and luminal markers. DVL3 cells formed tumours with distinct glandular morphology which expressed androgen receptor, similar to human localised PC. DVL3 tumour growth was delayed following administration of fractionated RT, with infiltration of myeloid derived suppressor cells (MDSC).Conclusions: The DVL3 allograft model represents substantial progress in PCa modelling, displaying; luminal differentiation, strong AR expression, and an immunosuppressive microenvironment, similar to observations in high-risk PCa patients. This model is ideally suited for development and validation of novel therapeutics, in particular immune-modulatory agents in combination with RT.
Original languageEnglish
TypeOnline preprint
Media of outputbioRxiv preprint server
DOIs
Publication statusPublished - 2020

Publication series

NamebioRxiv
PublisherCold Spring Harbor Laboratory Press

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