Development of a translational radiobiology platform using pancreatic cancer patient-derived organoids for personalized radiation oncology

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with neoadjuvant radio(chemo)therapy failing in approximately 70 % of cases due to high tumor heterogeneity, and intrinsic radioresistance. Patient-derived organoids (PDOs) closely recapitulate appearance, and functionality as the original tissue and have potential to explore novel therapies for personalized radiooncology. In this study, the radioresponse of PDAC PDO lines was determined after irradiation (RT). PDOs were immunohistochemically characterized by γ-H2AX, HIF-1α and Ki-67 staining. RNA sequencing data were analyzed by gene set enrichment analyses to investigate underlying mechanisms of radioresistance. Preclinical findings were correlated with clinical data from the corresponding patients. PDOs showed a significant heterogeneity in response to radiation and were classified into radiosensitive, intermediate, and radioresistant subgroups. A correlation between radiosensitivity and enhanced proliferation and decreased hypoxia was observed. OXPHOS-related gene signatures were significantly overexpressed in the radioresistant phenotype. Translationally, radioresistance in PDOs was associated with significantly poorer survival of patients. Our platform demonstrated heterogeneity in radioresponse reflecting the clinical situation and correlation with clinical outcomes. Immunohistochemical staining and transcriptomic profiling identified molecular signatures, including HIF-1α and OXPHOS-related pathways, associated with radioresistance. Implementing PDO-based radioresponse profiling in clinical workflows may enable patient stratified treatment approaches. Overall, our findings suggest that functionalizing PDOs for radioresponse might extend PDO-informed precision oncology.