Joanne C. McGrail

TP53 loss initiates chromosomal instability in fallopian tube epithelial cells

ABSTRACT High-grade serous ovarian cancer (HGSOC) originates in the fallopian tube epithelium and is characterized by ubiquitous TP53 mutation and extensive chromosomal instability (CIN). However, direct causes of CIN, such as mutations in DNA replication and mitosis genes, are rare in HGSOC. We therefore asked whether oncogenic mutations that are common in HGSOC can indirectly drive CIN in non-transformed human fallopian tube epithelial cells. To model homologous recombination deficient HGSOC, we sequentially mutated TP53 and BRCA1 then overexpressed MYC. Loss of p53 function alone was sufficient to drive the emergence of subclonal karyotype alterations. TP53 mutation also led to global gene expression changes, influencing modules involved in cell cycle commitment, DNA replication, G2/M checkpoint control and mitotic spindle function. Both transcriptional deregulation and karyotype diversity were exacerbated by loss of BRCA1 function, with whole-genome doubling events observed in independent p53/BRCA1-deficient lineages. Thus, our observations indicate that loss of the key tumour suppressor TP53 is sufficient to deregulate multiple cell cycle control networks and thereby initiate CIN in pre-malignant fallopian tube epithelial cells. This article has an associated First Person interview with the first author of the paper.

Screening a living biobank identifies cabazitaxel as a strategy to combat acquired taxol resistance in high-grade serous ovarian cancer

The anti-mitotic agent taxol (paclitaxel) remains a cornerstone of ovarian cancer treatment. To tackle drug resistance and toxicity, second-generation targeted anti-mitotic agents and combination strategies are being explored but have yet to demonstrate meaningful clinical benefits. A limitation is the lack of a platform to compare strategies in models that capture disease heterogeneity. To overcome this, we screen 83 patient-derived ex vivo ovarian cancer models that exhibit extensive intra- and inter-patient heterogeneity, testing four distinct approaches to enhance taxol sensitivity. Inhibitors of the HSET kinesin or the Mps1 spindle assembly checkpoint kinase show minimal impact on the taxol sensitivity landscape. By contrast, Bcl-xL inhibition exerts a global anti-proliferative effect. Inhibition of the MDR1 drug efflux pump restores taxol sensitivity in models characterized by ABCB1 overexpression. These MDR1-driven resistant models also respond to cabazitaxel, which is a poor MDR1 substrate, highlighting a potential therapeutic option for ovarian cancers with acquired taxol resistance.