A living biobank of ovarian cancer ex vivo models reveals profound mitotic heterogeneity
Louisa Nelson, Anthony Tighe, Anya Golder, Samantha Littler, Björn Bakker, Daniela Moralli, Syed Murtuza Baker, Ian J. Donaldson, Diana C.J. Spierings, René Wardenaar, Bethanie Neale, George J. Burghel, Brett Winter‐Roach, Richard J. Edmondson, Andrew R. Clamp, Gordon C. Jayson, Sudha Desai, Catherine Green, Andrew Hayes, Floris Foijer, Robert D. Morgan, Stephen S. Taylor
Abstract
High-grade serous ovarian carcinoma is characterised by TP53 mutation and extensive chromosome instability (CIN). Because our understanding of CIN mechanisms is based largely on analysing established cell lines, we developed a workflow for generating ex vivo cultures from patient biopsies to provide models that support interrogation of CIN mechanisms in cells not extensively cultured in vitro. Here, we describe a "living biobank" of ovarian cancer models with extensive replicative capacity, derived from both ascites and solid biopsies. Fifteen models are characterised by p53 profiling, exome sequencing and transcriptomics, and karyotyped using single-cell whole-genome sequencing. Time-lapse microscopy reveals catastrophic and highly heterogeneous mitoses, suggesting that analysis of established cell lines probably underestimates mitotic dysfunction in advanced human cancers. Drug profiling reveals cisplatin sensitivities consistent with patient responses, demonstrating that this workflow has potential to generate personalized avatars with advantages over current pre-clinical models and the potential to guide clinical decision making.