Abstract
Patient-derived organoid models are proving to be a powerful platform for both basic and translational studies. Here we conduct a methodical analysis of pancreatic ductal adenocarcinoma (PDAC) tumor organoid drug response in paired patient-derived xenograft (PDX) and PDX-derived organoid (PXO) models grown under WNT-free culture conditions. We report a specific relationship between area under the curve value of organoid drug dose response and in vivo tumor growth, irrespective of the drug treatment. In addition, we analyzed the glycome of PDX and PXO models and demonstrate that PXOs recapitulate the in vivo glycan landscape. In addition, we identify a core set of 57 N-glycans detected in all 10 models that represent 50%–94% of the relative abundance of all N-glycans detected in each of the models. Last, we developed a secreted biomarker discovery pipeline using media supernatant of organoid cultures and identified potentially new extracellular vesicle (EV) protein markers. We validated our findings using plasma samples from patients with PDAC, benign gastrointestinal diseases, and chronic pancreatitis and discovered that 4 EV proteins are potential circulating biomarkers for PDAC. Thus, we demonstrate the utility of organoid cultures to not only model in vivo drug responses but also serve as a powerful platform for discovering clinically actionable serologic biomarkers.
Highlights
Translational cancer research has benefited significantly from the use of patient materials either for genomics analysis or for the generation of patient tumor-derived models such as xenograft (PDX) or organoid cultures [1]
We conduct a methodical analysis of pancreatic ductal adenocarcinoma (PDAC) tumor organoid drug response in paired patient-derived xenograft (PDX) and PDX-derived organoid (PXO) models grown under WNT-free culture conditions
We reported that our WNT-free pancreas tumor organoid media (PTOM) was effective in retaining both the in vivo differentiation status of the patient tumor and the intratumor histological heterogeneity, demonstrating the potential to retain in vivo–relevant tumor biological traits in culture
Summary
Translational cancer research has benefited significantly from the use of patient materials either for genomics analysis or for the generation of patient tumor-derived models such as xenograft (PDX) or organoid cultures [1]. PDX models are known to maintain multiple aspects of cancer traits and model therapeutic drug response in patients with more than 85% accuracy [2] Despite their high fidelity in modeling human cancer, routine use of PDX models for all aspects of translational research is impeded by their high cost and the extended time needed to conduct experiments.
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