Radiation-Induced Resistance in Triple-Negative Breast Cancer Organoids: Decoding the Role of Dose Fractionation and the Tumour Microenvironment in Precision Radiotherapy

Objective

Radiotherapy fails in up to 40% of triple-negative breast cancer (TNBC) patients due to radioresistance mechanisms that remain poorly understood. RIoBORG (Radiation-Induced Resistance in Breast Cancer Organoids) addresses this urgent challenge using patient-derived xenograft organoids (PDXOs) as physiologically relevant models to study tumour-intrinsic and microenvironment-driven resistance. This translational project advances PDXO applications by integrating clinically relevant fractionated RT protocols with advanced tumour microenvironment (TME) modelling. The study simulates clinical RT regimens under normoxic and hypoxic conditions to capture tumour heterogeneity. A novel 3D co-culture system combining PDXOs with stromal and endothelial cells will enable in-depth investigation of angiogenesis, inflammation, and hypoxia-induced radioresistance—key factors often overlooked in conventional models. A multi-modal strategy, encompassing functional assays, molecular phenotyping, and transcriptomic analysis, will facilitate the identification of radiosensitivity-associated signatures and predictive biomarkers in PDXOs. Expected outputs include RT response profiles, biomarker panels, and stratification models that inform personalized treatment planning. The fellowship is strengthened by the host’s expertise in organoid and molecular profiling platforms and complemented by the fellow’s background in radiobiology, immunology, and bioinformatics. This synergy ensures interdisciplinary training aligned with MSCA goals and impactful research to improve personalized RT strategies in TNBC care.