Modeling clinical radioiodine uptake by using organoids derived from differentiated thyroid cancer

Abstract Radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) accounts for the vast majority of thyroid-related mortality and, until recently, there were limited preclinical models for iodine uptake prediction. In the current study, we aim to establish a primary tumor-derived organoid model of DTC and predict radioiodine (RAI) uptake of tumor residue. The genotypic and phenotypic features between organoid and parental tissue were compared. The RAI uptake assay was used to evaluate the organoid's RAI uptake capacity, and related patients' RAI whole-body scans were used to verify the assay's predictive sensitivity. A total of 20 patient-derived DTC organoids have been established. Whole-exome sequencing and immunofluorescence analysis demonstrated that organoids faithfully recapitulated main features of the original tumor tissue. RAI-avid organoids (n = 11) presented significantly higher RAI uptake than the RAI-refractory (RAI-R) group (n = 9; 384.4 ± 102.7 vs 54.2 ± 13.2 cpm/105 cells, P < .0001). A threshold value in organoids of less than 250 cpm/105 cell was found to have a predictive sensitivity of 95.0% for distinguishing RAI-R from RAI-avid patients when paired to clinical information. Notably, we found that several tyrosine kinase inhibitors moderately re-sensitize iodine uptake by using organoids derived from 3 patients with different genetic mutation backgrounds. In conclusion, patient-derived DTC organoids recapitulated the main characteristics of their parental tissues and preserved ability to uptake radioiodine, showing potential in the development of novel drugs to boost iodine avidity.