PDX-derived organoids model in vivo drug response and secrete biomarkers
- PMID: 32990680
- PMCID: PMC7710298
- DOI: 10.1172/jci.insight.135544
Free PMC article
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.
Keywords: Cancer; Glycobiology; Oncology.
Conflict of interest statement
Conflict of interest: LH and SKM have a patent application pending for the pancreas tumor organoid media used in this study (US20170267977A1). BB received research funding from NanoView Biosciences. MH has stock and ownership interests in Champions Oncology, PharmaCyte Biotech, Bioncotech, Nelum, and Agenus; his honoraria include Takeda, Agenus, InxMed, PharmaCyte Biotech, Bioncotech, Tolero, Novartis, Oncomatrix, and KAHR Medical; he has a consulting or advisory role for Takeda, Agenus, InxMed, PharmaCyte Biotech, Bioncotech, Tolero, Novartis, Oncomatrix, and KAHR Medical; his patents, royalties, and other intellectual property include Myriad Genetics.