3D culture of patient-derived tumour tissue offers a route to personalized cancer treatment whereby potential drugs can be screened ex vivo to stratify the optimal care plans. Such treatment stratification can predict patient responsiveness and adverse effects, with a view to streamlining first-line drug selection. Appropriate patient-derived 3D models need to show biomimicry to the in vivo biology of the patient of origin, replicating relevant tissue architecture, biomarker levels, cellular organisation pathways that allow accurate response testing of drugs.
11 Gleason 7 prostate cancer patients were recruited & their tissue underwent MRI-guided bio-banking, following radical prostatectomy, using the PEOPLE method. Matched specimens were cultured as gelatin sponge explants for all patients for 72 hours. Resulting samples were segmented into epithelial vs. non-epithelial compartments via PanCK staining before undergoing whole genome spatial transcriptomics analysis. Spatial RNA expression analysis was performed for a total of 17299 genes for each patient.
Epithelial analysis reveals architectural maintenance of core basal, luminal and neuroendocrine prostate epithelium post-culture. Non-epithelial analysis showed maintenance of the immune landscape and vascular coverage. However, the 72-hour cultured samples showed an increase in key ECM degradation markers including MMPs and ADAMTS family genes. Overall, a reduction was seen post-culture in key growth pathways and drug targets including AR-response, WNT/Beta-catenin and PI3K/AKT/mTOR genes with an increase in apoptotic markers.
This is the first study to date which provides in-depth tissue-compartmentally segmented transcriptomic analysis of 3D cultured primary prostate cancer, offering an insight into the biomimicry of such ex vivo 3D models and their potential in clinical drug screening applications. This study showed that while epithelial architecture was preserved, key drug-target pathways involved in tumour cell growth and viability were less active following culture, suggesting improvements are needed to ensure accurate drug responses that mimic the outcome in matched patients.
The authors.
Prostate Cancer UK.
All authors have declared no conflicts of interest.