Patient-Derived Papillary Thyroid Cancer Organoids for Radioactive Iodine Refractory Screening

SIMPLE SUMMARY: Over the past three decades, the incidence of thyroid cancer has been rising, with 90% being the well-differentiated thyroid cancer subtype. After diagnosis and surgical removal of the thyroid gland, radioactive iodine is administered to induce a localized post-operative radiation treatment. However, in 15-33% of papillary thyroid cancer cases, the cells are unable to take up radioactive iodine, resulting in an ineffective treatment which sometimes has severe side effects. Pre-treatment diagnosis of non-responding patients would prevent ineffective and toxic iodine treatment. Therefore, in this study, we developed a patient-derived papillary thyroid cancer organoid model. Patient-derived organoids responding or not responding to radioactive iodine clearly resembled the tumor of origin, but showed clear differences in sodium/iodide symporter expression. Our results indicate that thyroid cancer organoids might be a suitable tool for the early diagnosis of non-responding patients, in order to eventually reduce radioactive iodine overtreatment and its many side effects for thyroid cancer patients. ABSTRACT: Patients with well-differentiated thyroid cancer, especially papillary thyroid cancer (PTC), are treated with surgical resection of the thyroid gland. This is followed by post-operative radioactive iodine (I(131)), resulting in total thyroid ablation. Unfortunately, about 15-33% of PTC patients are unable to take up I(131), limiting further treatment options. The aim of our study was to develop a cancer organoid model with the potential for pre-treatment diagnosis of these I(131)-resistant patients. PTC tissue from thirteen patients was used to establish a long-term organoid model. These organoids showed a self-renewal potential for at least five passages, suggesting the presence of cancer stem cells. We demonstrated that thyroid specific markers, a PTC marker, and transporters/receptors necessary for iodine uptake and thyroid hormone production were expressed on a gene and protein level. Additionally, we cultured organoids from I(131)-resistant PTC material from three patients. When comparing PTC organoids to radioactive iodine (RAI)-refractory disease (RAIRD) organoids, a substantial discordance on both a protein and gene expression level was observed, indicating a treatment prediction potential. We showed that patient-derived PTC organoids recapitulate PTC tissue and a RAIRD phenotype. Patient-specific PTC organoids may enable the early identification of I(131)-resistant patients, in order to reduce RAI overtreatment and its many side effects for thyroid cancer patients.