Project description:We performed single-cell RNA-sequencing of 54,762 cells derived from normal thyroid tissue from 7 patients, revealing distinct cell types including epithelial cells, fibroblasts, endothelial cells, smooth muscle cells/pericytes, and various immune cells.
Project description:We performed single-cell RNA sequencing (scRNA-seq) on 3 normal thyroid, 7 papillary thyroid cancer (PTC), and 5 anaplstic thyroid cancer (ATC) cases. We used scRNA-seq to analyze serirne/glycine metabolism in thyroid tumors.
Project description:The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with very high mortality. Double-stranded RNA–directed RNA interference (dsRNAi) targeting the PIAS2 isoform beta (PIAS2b) inhibits growth of ATC cell lines and patient primary cultures in vitro and orthotopic patient-derived xenografts (oPDX) in vivo, but not of thyroid cell lines or non-anaplastic primary thyroid cultures (differentiated carcinoma, benign lesions, or normal). PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. Strikingly, PIAS2b-dsRNAi induces mitotic catastrophe at prophase. High-throughput proteomics revealed the proteasome (PSMC5) and spindle cytoskeleton as direct targets of PIAS2b SUMOylation at mitotic initiation. PIAS2b-dsRNAi is a promising therapy for ATC and other aggressive anaplastic cancers.
Project description:The thyroid gland regulates metabolism and growth via secretion of thyroid hormone by thyroid follicular cells (TFCs). Loss of TFCs, by cellular dysfunction, autoimmune destruction or surgical resection, underlies hypothyroidism. Recovery of thyroid hormone levels by transplantation of mature TFCs derived from stem cells in vitro holds great therapeutic promise. However, the utilization of in vitro derived tissue for regenerative medicine is restricted by the efficiency of differentiation protocols to generate mature organoids. Here, to improve the differentiation efficiency for thyroid organoids, we utilized single-cell RNA-Seq to chart the molecular steps undertaken by individual cells during the in vitro transformation of mouse embryonic stem cells to TFCs. Our single-cell atlas of mouse organoid systematically and comprehensively identifies, for the first time, the cell-types generated during production of thyroid organoids. Using pseudotime analysis, we identify molecular pathways that regulate thyroid maturation in vitro. Our study highlights the potential of single-cell molecular characterization in understanding and improving thyroid maturation, and paves the way for identification of therapeutic targets against thyroid disorders.
Project description:The thyroid gland is responsible for supplying the thyroid hormones to the body. The gland is an endocrine organ with an intricate structure enabling production, storage and release of the thyroid hormones. The gland is composed of numerous spherical follicles of varying sizes, surrounded by thyroid follicular epithelial cells, or thyrocytes. The thyrocytes surrounding the follicles generate the thyroid hormones in a multi-step process. Though the machinery responsible for the production of thyroid hormones by thyrocytes is well established, it remains unknown if all the thyrocytes resident in the thyroid gland are equally capable of generating thyroid hormones. In other words, the extent of molecular homogeneity between individual thyrocytes has not yet been investigated. To obtain an unbiased picture into the molecular heterogeneity present in zebrafish thyrocytes, we performed droplet based next-generation sequencing of individual thyrod gland cells. Using unsupervised clustering, we could identify all the major cell types present in the thyroid gland. Moreover, we could define sub-populations within the major cell-types, demonstrating the presence of molecular heterogeneity within nominally homogenous cell-populations.
Project description:The function of the thyroid gland is to metabolize iodide to synthesize hormones that act on almost all tissues and are essential for normal growth and metabolism. Low plasma levels of thyroid hormones lead to hypothyroidism, which is one of the most common diseases in the general population and cannot be always satisfactorily treated by lifelong hormone replacement. Therefore, in addition to the lack of in vitro tractable models to study human thyroid development, differentiation and maturation, there is a need for new therapeutic approaches that involve replacement of thyroid tissue to better control hormone balance. Here we report the first model of thyroid organoids derived from human embryonic stem cells that produce thyroid hormones in vitro and are capable of restoring plasma thyroid hormone levels when transplanted into athyreotic mice.