Biology subjects

Coulson-Gilmer, C.

Publications and source records attributed to Coulson-Gilmer, C..

3 recordsLinked to original sources

bioRxiv2026

Sexual Dimorphism of Cancer-Associated Fibroblasts Governs Matrix and Vascular Organisation in Breast Cancer

Breast cancer (BC) shows greatest sexual diversity. Increased diagnosis and poorer outcomes in men highlights the need to better understand its biology. We hypothesised that cancer-associated fibroblasts (CAFs), the most abundant cell type in the tumour microenvironment, might define sex-related differences. Using phenotypically matched male and female CAFs generated from breast cancer tissues, we demonstrate distinct transcriptional programmes and functional behaviours associated with extracellular matrix remodelling, cell adhesion, migration and vascular development. Compared to CAFs generated from females BC, those from males generated denser, more complex matrices promoting stronger tumour and endothelial cell adhesion, vascular growth, but less organised capillary network formation. Findings reveal fundamental sex-related variations in CAF phenotype and biology in BC. These findings highlight the need to integrate biological sex into precision oncology to identify opportunities for sex-specific therapeutic strategies in BC.

cancer biology↗

bioRxiv2025

Exploring CDK4/6-Dependencies in ex vivo Ovarian Cancer Models

Ovarian cancer (OC) is a clinically and molecularly heterogeneous disease with limited treatment options for the majority of patients, particularly those with homologous-recombination-proficient high-grade serous ovarian cancer (HGSOC) and rarer subtypes such as low-grade serous ovarian cancer. Deregulation of the G1/S cell cycle network is common across all subtypes, suggesting subtype-agnostic vulnerabilities. Here, we assessed CDK4/6 dependency using the selective inhibitor palbociclib across 20 patient-derived ex vivo OC models. A subset of models, including four HGSOC and six rarer subtypes, exhibited marked sensitivity to palbociclib, characterised by low CDKN2A/CDKN2B expression, Rb hypophosphorylation, and G1 cell cycle arrest. In contrast, resistant models showed high CDKN2A expression and reduced or absent RB1. Notably, ABCB1 overexpression--a known resistance mechanism in OC--did not mediate palbociclib resistance. Analysis of longitudinal models revealed diminished CDK4/6 dependency following treatment, accompanied by increased CDKN2A expression. These findings support a model of G1/S control in which tumours diverge into CDK4/6- or CDK2-driven proliferation states, with CDKN2A as a potential biomarker to guide patient selection. The predominance of CDK4/6-inhibitor-resistant HGSOC highlights a priority population for CDK2-targeted therapies, offering new treatment strategies for patients with otherwise limited options.

cancer biology↗

bioRxiv2020

PARG inhibition induces replication catastrophe in ovarian cancer cells with down-regulated DNA replication genes

The discovery that PARP1/2 inhibitors selectively kill BRCA mutant cells has led to a paradigm shift in the treatment of women with homologous recombination (HR)-deficient high-grade serous ovarian cancer (HGSOC), driving unprecedented improvements in progression-free and, more recently, overall survival. However, because most HGSOC cases are not HR-defective, and are therefore unlikely to benefit from PARPi-based therapies, additional strategies will be required to improve outcomes for women with HR-proficient disease. To develop novel therapeutic strategies, considerable attention is now being focused on inhibitors targeting PARG, the poly(ADP ribose) glycohydrolase that counterbalances PARP1/2 activity. Here we characterise ten ovarian cancer cell lines in response to the PARG inhibitor PDD00017273, hereafter PARGi. We demonstrate that six lines are resistant while four are sensitive, and that sensitivity correlates with several markers of persistent DNA replication stress, DNA damage and replication catastrophe, namely the accumulation of asymmetric DNA replication fibres, {gamma}H2AX and RPA foci, KAP1 and Chk1 phosphorylation, a pre-mitotic cell cycle block and, following prolonged exposure, a pan-nuclear {gamma}H2AX phenotype that indicates RPA exhaustion. We demonstrate that PARGi-sensitive cell lines have down-regulated DNA replication genes, including components of the fork protection complex, namely TIMELESS, TIPIN and CLASPIN. These observations suggest that a subset of HGSOC may respond to PARG inhibitors and that "replication stress" gene expression signature could serve as a predictive biomarker to guide the design of clinical trials.

cancer biology↗