Patient-derived parathyroid organoids as tracer and drug-screening application model
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ABSTRACT:
PROVIDER: PRJNA810360 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18139000.fastq.gz | Fastqsanger.gz | |||
| SRR18139001.fastq.gz | Fastqsanger.gz | |||
| SRR18139002.fastq.gz | Fastqsanger.gz | |||
| SRR18139003.fastq.gz | Fastqsanger.gz | |||
| SRR18139004.fastq.gz | Fastqsanger.gz |
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Project description:Parathyroid diseases are characterized by dysregulation of calcium homeostasis and alterations in parathyroid hormone (PTH) excretion. The understanding of parathyroid hyperplastic growth and the development of tracers for imaging and treatment could benefit from in vitro models. Therefore, we aim to establish stem cell-derived three-dimensional organoids representing human parathyroid tissue in vitro. Patient-derived hyperplastic parathyroid tissue was dispersed and parathyroid organoids (PTO) were cultured, characterized by immunofluorescence, and RNA-sequencing was performed. Functional PTO testing was performed by calcium-response measurements, drug screening, PET (11C-methionine) and SPECT-tracer (99mTc-sestamibi) validation. PTO in vitro self-renewal potential was assessed to show the presence of putative stem cells. RNA-sequencing confirms that PTO phenocopy hyperplastic parathyroid tissue. Exposure to increasing calcium concentrations and to PTH-lowering drugs, resulted in a significantly reduced PTH excretion. Next to this, the PTO showed specific binding of 11C-methionine to the targeted receptor. Additionally, when organoids were incubated with 99mTc-sestamibi, we observed a higher uptake in PTOs from patients with a positive scan compared to patients with a negative scan. In conclusion, we present a patient-derived PTO culture, that recapitulates the originating tissue on gene and protein expression and functionality. We demonstrate the potential of PTOs for physiology studies and therapeutic target and tracer discovery.
2022-02-28 | GSE197445 | GEO
Project description:Parathyroid diseases are characterized by dysregulation of calcium homeostasis and alterations in parathyroid hormone (PTH) excretion. The development of parathyroid-targeted treatment and imaging tracers could benefit from in vitro models. Therefore, we aim to establish a patient-derived parathyroid organoid model representing human parathyroid tissue. Hyperplastic parathyroid tissue was dispersed, and parathyroid organoids (PTOs) were cultured and characterized. PTO-derived cells exhibited self-renewal over several passages, indicative of the presence of putative stem cells. Immunofluorescence and RNA sequencing confirmed that PTOs phenocopy hyperplastic parathyroid tissue. Exposure of PTOs to increasing calcium concentrations and PTH-lowering drugs resulted in significantly reduced PTH excretion. PTOs showed specific binding of the imaging tracers 11C-methionine and 99mTc-sestamibi. These data show the functionality of PTOs resembling the parathyroid. This PTO model recapitulates the originating tissue on gene and protein expression and functionality, paving the way for future physiology studies and therapeutic target and tracer discovery.
| S-EPMC9669499 | biostudies-literature
Project description:Primary hyperparathyroidism is a common endocrine disorder frequently affecting postmenopausal women. In this study we have investigated expression of the prolactin receptor (PRLr) in a panel of 37 sporadic parathyroid tumours, as well as functionality in vitro in cultured parathyroid tumour cells. High levels of the prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues as compared to other reference tissues and breast cancer cells. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours PRLr immunoreactivity was observed in cytoplasm in all cases and in addition in the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim PRLr was expressed in cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells prolactin stimulation was associated with transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signaling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumors was significantly inversely correlated with plasma total Ca2+ levels. In conclusion, the prolactin receptor was found highly abundant in human parathyroid gland, parathyroid tumours, correlated with patient Ca2+ levels and functionally responsive to physiological levels of prolactin. These findings suggest a role for the prolactin receptor in human parathyroid adenomas.
2012-05-01 | GSE32387 | GEO
Project description:As a polyphenolic herbal extract, Gallic acid (GA) is known for its antioxidant and anti-inflammatory properties. However, its application in parathyroid ischemia-reperfusion injury (IRI) has not been well examined. This study aimed to elucidate the protective effects of GA pretreatment in a parathyroid IRI model and explore the underlying mechanisms.Hypoxia and hypoxia/reoxygenation models were established with primary parathyroid cells to explore the protective effect of GA.The results from sequencing and bioinformatic analyses indicated that GA might regulate MMP1, MMP9, FOSB, GSY2, DUSP5, TRPV1/3, TIAM1 and multiple signaling pathways in this process such as IL-17, AMPK, MAPK, Transient Receptor Potential (TRP) channels, cAMP and Rap1.
2023-08-23 | GSE240162 | GEO
Project description:Primary hyperparathyroidism is a common endocrine disorder frequently affecting postmenopausal women. In this study we have investigated expression of the prolactin receptor (PRLr) in a panel of 37 sporadic parathyroid tumours, as well as functionality in vitro in cultured parathyroid tumour cells. High levels of the prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues as compared to other reference tissues and breast cancer cells. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours PRLr immunoreactivity was observed in cytoplasm in all cases and in addition in the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim PRLr was expressed in cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells prolactin stimulation was associated with transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signaling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumors was significantly inversely correlated with plasma total Ca2+ levels. In conclusion, the prolactin receptor was found highly abundant in human parathyroid gland, parathyroid tumours, correlated with patient Ca2+ levels and functionally responsive to physiological levels of prolactin. These findings suggest a role for the prolactin receptor in human parathyroid adenomas. Expression profiling was done in parathyroid adenomas subjected to prolactin treatment in culture. In addition, corresponding paraffin sections were obtained for verification of PRLr expression by immunohistochemistry. 200 mg/L prolactin (recombinant humanM-BM- prolactin, Cat. No. JM-4687-50, MBL Woburn, MA) was added to 1M-CM-^W 10^6 attached parathyroid tumour cells. Cells were harvested using RNAlater (QIAGEN) and homogenized with QIAshredder for RNA extraction after 3 h and 24 h in culture, respectively. Negative controls were collected in parallel with each case at the same time points. RNA was extracted using QIA Cube, and quality assessed with Bioanalyser and Nanodrop. Expression array profiling and data analysis was done at the KI core facility Bioinformatics and Expression Analysis (BEA, Novum, Huddinge) using the Affymetrix platform and the TITAN ST 1.1 array. A total of 16 samples were analysed including 4 parathyroid adenomas cultured for 3 h or 24 h in the presence of prolactin plus control samples cultured in parallel without prolactin.
2012-04-30 | E-GEOD-32387 | biostudies-arrayexpress
Project description:Transcriptional profiling of genes expressed in normal parathyroid glands (Normal) and adenomatous parathyroid glands from patients with primary hyperparathyroidism (PHPT). Stratagen Human Refernece RNA, pooled from 10 human cell lines, was used to identify genes, which are specifically expressed or suppressed in parathyroid tissue. Comparison between normal and tumor parathyroids shows genes that might be involved in hyperproliferation and PTH hypersecretion in tumors.
2016-12-01 | GSE83421 | GEO
Project description:We genetically characterized parathyroid adenomas with large glandular weights, for which independent observations suggest pronounced clinical manifestations. Large parathyroid adenomas (LPTAs) were defined as the 5% largest sporadic parathyroid adenomas identified among the 590 cases operated on in our institution during 2005-2009. The LPTA group showed a higher relative number of male cases and significantly higher levels of total plasma and ionized serum calcium (P <0.001). Further analysis of 21 LPTAs revealed low MIB-1 proliferation index (0.1-1.5%), MEN1 mutations in 5 cases and one HRPT2 mutation. Total or partial loss of parafibromin expression was observed in 10 tumors, two of which also showed loss of APC expression. Using array-CGH, we demonstrated recurrent copy number alterations most frequently involving loss in 1p (29%), gain in 5 (38%) and loss in 11q (33%). Totally 21 minimal overlapping regions were defined for losses in 1p, 7q, 9p, 11 and 15q, and gains in 3q, 5, 7p, 8p, 16q, 17p and 19q. In addition, 12 tumors showed gross alterations of entire or almost entire chromosomes, most frequently gain of 5 and loss of 11. While gain of 5 was the most frequent alteration observed in LPTAs, it was only detected in a small proportion (4/58 cases, 7%) of parathyroid adenomas. A significant positive correlation was observed between parathyroid hormone level and total copy number gain (r = 0.48, P = 0.031). These results support that LPTAs represent a group of patients with pronounced parathyroid hyperfunction and associated with specific genomic features. We applied high-resolution array-CGH to assess copy number alterations (CNAs) in 21 tumors representing the 5% largest sporadic parathyroid adenomas in our institution.
2012-05-08 | E-GEOD-36511 | biostudies-arrayexpress
Project description:Application of the transcriptomic biomarker, TGx-DDI, in genotoxicity screening
| PRJNA419190 | ENA
Project description:Pulmonary hypertension (PH) is an incurable right heart failure disease. Parathyroid hormone (PTH) is secreted from the parathyroid gland and plays a crucial role in calcium homeostasis. PTH also acts on the cardiovascular system and affects cardiovascular prognosis. We assessed whether the regulation of PTH affected PH in a hypoxia (Hx)-induced PH mouse model. PTH treatment exacerbated right ventricular hypertrophy and right ventricular systolic pressure in Hx mice. Our data showed how is PTH effected for PH model murine lung.
2023-10-11 | GSE244861 | GEO
Project description:BackgroundGallbladder carcinoma (GBC) is a relatively rare but highly aggressive cancer with late clinical detection and a poor prognosis. However, the lack of models with features consistent with human gallbladder tumours has hindered progress in pathogenic mechanisms and therapies.MethodsWe established organoid lines derived from human GBC as well as normal gallbladder and benign gallbladder adenoma (GBA) tissues. The histopathology signatures of organoid cultures were identified by H&E staining, immunohistochemistry and immunofluorescence. The genetic and transcriptional features of organoids were analysed by whole-exome sequencing and RNA sequencing. A set of compounds targeting the most active signalling pathways in GBCs were screened for their ability to suppress GBC organoids. The antitumour effects of candidate compounds, CUDC-101 and CUDC-907, were evaluated in vitro and in vivo.ResultsThe established organoids were cultured stably for more than 6 months and closely recapitulated the histopathology, genetic and transcriptional features, and intratumour heterogeneity of the primary tissues at the single-cell level. Notably, expression profiling analysis of the organoids revealed a set of genes that varied across the three subtypes and thus may participate in the malignant progression of gallbladder diseases. More importantly, we found that the dual PI3K/HDAC inhibitor CUDC-907 significantly restrained the growth of various GBC organoids with minimal toxicity to normal gallbladder organoids.ConclusionsPatient-derived organoids are potentially a useful platform to explore molecular pathogenesis of gallbladder tumours and discover personalized drugs.
| S-EPMC8786696 | biostudies-literature