TY - JOUR
T1 - A living biobank of ovarian cancer ex vivo models reveals profound mitotic heterogeneity
AU - Nelson, Louisa
AU - Tighe, Anthony
AU - Golder, Anya
AU - Littler, Samantha
AU - Bakker, Bjorn
AU - Moralli, Daniela
AU - Baker, Syed Murtuza
AU - Donaldson, Ian
AU - Spierings, Diana C J
AU - Wardenaar, Rene
AU - Neale, Bethanie
AU - Burghel, George
AU - Winter-Roach, Brett
AU - Edmondson, Richard
AU - Clamp, Andrew
AU - Jayson, Gordon
AU - Desai, Sudha
AU - Green , Catherine M
AU - Hayes, Andrew
AU - Foijer, Floris
AU - Morgan, Robert
AU - Taylor, Stephen
PY - 2020/2/13
Y1 - 2020/2/13
N2 - 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 capcity, 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.
AB - 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 capcity, 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.
KW - Biological Specimen Banks
KW - Chromosomal Instability
KW - Drug Resistance, Neoplasm
KW - Female
KW - Gene Expression
KW - Gene Expression Profiling
KW - Histological Techniques/methods
KW - Humans
KW - Imaging, Three-Dimensional
KW - In Situ Hybridization, Fluorescence
KW - In Vitro Techniques
KW - Karyotyping
KW - Mitosis/genetics
KW - Models, Biological
KW - Mutation
KW - Ovarian Neoplasms/drug therapy
KW - Paclitaxel/pharmacology
KW - Single-Cell Analysis
KW - Time-Lapse Imaging
KW - Tumor Suppressor Protein p53/genetics
KW - Whole Exome Sequencing
U2 - 10.1038/s41467-020-14551-2
DO - 10.1038/s41467-020-14551-2
M3 - Article
C2 - 32054838
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 822
ER -