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Context Exosomal miRNAs are considered potential non-invasive biomarkers for thyroid cancer. However, the global exosomal miRNAs profile for papillary thyroid cancer (PTC) has not been revealed. Objective This study investigated the diagnostic value of plasma and serum exosomal miRNAs for PTC. Methods Plasma and serum samples were collected from ten patients with benign thyroid nodules and 17 with PTC for small RNA sequencing. Plasma samples were collected from two independent cohorts, including 119 patients with PTC, 51 healthy people and 82 patients with benign thyroid nodules, for validation by quantitative reverse-transcription polymerase chain reaction (RT-qPCR). Results Small RNA sequencing identified 41 putative exosomal miRNA biomarkers for PTC. Twelve miRNAs were selected for validation. miR-376a-3p, miR-4306, miR-4433a-5p, and miR-485-3p expression significantly increased in patients with PTC compared to that in healthy people and patients with benign thyroid nodules (P ˂ 0.05). Moreover, miR-485-3p and miR-4433a-5p presented larger areas under the curve (AUCs). The high expression of exosomal miR-485-3p correlated with tumor size greater than or equal to 1 cm, advanced clinical stage, extrathyroidal extension, BRAF mutation, and lymph node metastasis. Besides, miR-485-3p exhibited the highest AUCs in diagnosing PTC patients with high-risk factors. Conclusions Plasma exosomal miR-485-3p and miR-4433a-5p might serve as biomarkers for PTC diagnosis. Plasma exosomal miR-485-3p could enable discrimination between high-risk and low-risk PTC.

Context Papillary thyroid cancer (PTC) has been one of the most frequent endocrine malignancies around the world. Although most PTC patients have a favorable prognosis, a subgroup of patients die, especially when disease recurrence occurs. There is a pressing need for clinically relevant preclinical thyroid cancer models for personalized therapy due to the lack of in vitro models that faithfully represent the biology of the parental tumors. Objective To understand thyroid cancer and translate this knowledge to clinical applications, the patient-derived PTC organoids as a promising new preclinical model were established. Design Surgically resected PTC primary tissues were dissociated and processed for organoid derivation. Tumor organoids were subsequently subjected to histological characterization, DNA-sequencing, drug screen, and cell proliferation assay, respectively. Results We describe a three-dimensional culture system for the long-term expansion of patient-derived PTC organoid lines. Notably, PTC organoids preserve the histopathological profiles and genomic heterogeneity of the originating tumors. Drug sensitivity assays of PTC organoids demonstrate patient-specific drug responses, and large correlations with the respective mutational profiles. Estradiol was shown to promote cell proliferation of PTC organoids in the presence of estrogen receptor α (ERα), regardless of the expression of estrogen receptor β (ERβ) and G protein-coupled estrogen receptor (GPER). Conclusions These data suggest that this newly developed PTC-derived organoids may be an excellent preclinical model for studying clinical response to anticancer drugs in a personalized way, as well as provide a potential strategy to develop the prevention and treatment options for thyroid cancer with ERα-specific antagonists.

Backgrounds Papillary thyroid cancer (PTC), which is often driven by acquired somatic mutations in BRAF genes, is the most common pathologic type of thyroid cancer. PTC has an excellent prognosis after treatment with conventional therapies such as surgical resection, thyroid hormone therapy and adjuvant radioactive iodine therapy. Unfortunately, about 20% of patients develop regional recurrence or distant metastasis, making targeted therapeutics an important treatment option. Current in vitro PTC models are limited in representing the cellular and mutational characteristics of parental tumors. A clinically relevant tool that predicts the efficacy of therapy for individuals is urgently needed. Methods Surgically removed PTC tissue samples were dissociated, plated into Matrigel, and cultured to generate organoids. PTC organoids were subsequently subjected to histological analysis, DNA sequencing, and drug sensitivity assays, respectively. Results We established 9 patient-derived PTC organoid models, 5 of which harbor BRAFV600E mutation. These organoids have been cultured stably for more than 3 months and closely recapitulated the histological architectures as well as mutational landscapes of the respective primary tumors. Drug sensitivity assays of PTC organoid cultures demonstrated the intra- and inter-patient specific drug responses. BRAFV600E inhibitors, vemurafenib and dabrafenib monotherapy was mildly effective in treating BRAFV600E-mutant PTC organoids. Nevertheless, BRAF inhibitors in combination with MEK inhibitors, RTK inhibitors, or chemotherapeutic agents demonstrated improved efficacy compared to BRAF inhibition alone. Conclusions These data indicate that patient-derived PTC organoids may be a powerful research tool to investigate tumor biology and drug responsiveness, thus being useful to validate or discover targeted drug combinations.