Pre-receptor regulation of 11-oxyandrogens differs between normal and cancerous endometrium and across endometrial cancer grades and molecular subtypes
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PROVIDER: PRJNA1297083 | ENA |
REPOSITORIES: ENA
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Project description:Background: Endometrial cancer (EC) is a prevalent gynecological malignancy globally, with a rising incidence trend. While classic androgens have been implicated with EC risk, the role of their 11-oxygenated metabolites is poorly understood. Here, we studied 11-oxyandrogen formation from steroid precursors in EC for the first time. Methods: We performed in vitro studies on a panel of four EC cell lines of varying differentiation degree and molecular subtype and a control cell line of normal endometrium to assess 11-oxyandrogen formation from steroid precursors. We also characterized the transcriptomic effects of dihydrotestosterone (DHT) and 11-keto-DHT on Ishikawa and RL95-2. Key molecular players in 11-oxyandrogen metabolism and action were explored in endometrial tumors using public transcriptomic datasets. Results: We discovered that within endometrial tumors, the formation of 11-oxyandrogens does not occur from classic androgen precursors. However, we observed distinct regulatory mechanisms at a pre-receptor level in normal endometrium compared to cancerous tissue, and between low- and high-grade tumors. Specifically, in vitro models of low-grade EC formed higher levels of bioactive 11-keto-testosterone from 11-oxyandrogen precursors compared to models of noncancerous endometrium and high-grade, TP53-mutated EC. Moreover, the potent androgen, DHT and its 11-keto homologue induced mild transcriptomic effects on androgen receptor (AR)-expressing EC model, Ishikawa. Finally, using public transcriptomic datasets, we found HSD11B2 and SRD5A2, coding for key enzymes in steroid metabolism, to be associated with better disease-specific survival, whereas higher intra-tumoral AR expression correlated with lower recurrence in TP53-wt tumors. Conclusions: The intra-tumoral metabolism of 11-oxyandrogen precursors is characteristic for low-grade EC of non-TP53-alt molecular subtypes. Our findings support further exploration of circulating 11-oxyandrogens as prognostic biomarkers in EC.
2025-07-26 | GSE303681 | GEO
Project description:BackgroundEndometrial cancer (EC) is a prevalent gynecological malignancy globally, with a rising incidence trend. While classic androgens have been implicated with EC risk, the role of their 11-oxygenated metabolites is poorly understood. Here, we studied 11-oxyandrogen formation from steroid precursors in EC for the first time.MethodsWe performed in vitro studies on a panel of four EC cell lines of varying differentiation degree and molecular subtype and a control cell line of normal endometrium to assess 11-oxyandrogen formation from steroid precursors. We also characterized the transcriptomic effects of dihydrotestosterone (DHT) and 11-keto-DHT on Ishikawa and RL95-2. Key molecular players in 11-oxyandrogen metabolism and action were explored in endometrial tumors using public transcriptomic datasets.ResultsWe discovered that within endometrial tumors, the formation of 11-oxyandrogens does not occur from classic androgen precursors. However, we observed distinct regulatory mechanisms at a pre-receptor level in normal endometrium compared to cancerous tissue, and between low- and high-grade tumors. Specifically, in vitro models of low-grade EC formed higher levels of bioactive 11-keto-testosterone from 11-oxyandrogen precursors compared to models of noncancerous endometrium and high-grade, TP53-mutated EC. Moreover, the potent androgen, DHT and its 11-keto homologue induced mild transcriptomic effects on androgen receptor (AR)-expressing EC model, Ishikawa. Finally, using public transcriptomic datasets, we found HSD11B2 and SRD5A2, coding for key enzymes in steroid metabolism, to be associated with better disease-specific survival, whereas higher intra-tumoral AR expression correlated with lower recurrence in TP53-wt tumors.ConclusionsThe intra-tumoral metabolism of 11-oxyandrogen precursors is characteristic for low-grade EC of non-TP53-alt molecular subtypes. Our findings support further exploration of circulating 11-oxyandrogens as prognostic biomarkers in EC.
| S-EPMC11349532 | biostudies-literature
Project description:Organoid technology has provided unique insights into human organ development, function, and diseases. Patient derived organoids are increasingly used for drug screening, modeling rare disorders, designing regenerative therapies, and understanding pathological changes associated with disease progression. However, the use of Matrigel to grow organoids represents a major challenge in the clinical translation of organoid technology. Matrigel is a poorly defined cocktail of extracellular matrix proteins and growth factors extracted from the Engelbreth Holm Swarm mouse tumor. The extracellular matrix is a major driver of multiple cellular processes and differs significantly between tissues as well as in healthy and diseases states of the same tissue. Therefore, we envisioned that extracellular matrix derived from a native healthy tissue would be sufficient to support organoid growth akin to organogenesis in vivo. Here, we have developed hydrogels from decellularized human and bovine endometrium. These hydrogels supported the growth of mouse and human endometrial organoids, which was comparable to Matrigel. Organoids grown in endometrial hydrogels were proteomically more similar to the native tissue than the organoids cultured in Matrigel. Proteomic and Raman spectroscopy analyses showed that the method of decellularization affects the biochemical composition of hydrogels and subsequently, their ability to support organoid growth. The amount of laminin in hydrogels correlated with the number and the shape of organoids. We also demonstrated the utility of endometrial hydrogels in developing solid scaffolds for supporting high throughput cell culture-based applications. In summary, endometrial hydrogels overcome a major limitation of organoid technology and greatly expand the applicability of organoids to understand endometrial biology and associated pathologies.
2022-03-14 | MSV000089054 | MassIVE
Project description:Successful embryo implantation into a receptive endometrium requires mutual endometrial-embryo communication. Recently, the function of extracellular vehicles (EVs) in cell-to-cell interaction in embryo-maternal interactions has been investigated. We explored isolated endometrial derived EVs, using RL95-2 cells as a model of a receptive endometrium, influenced by menstrual cycle hormones estrogen (E2; proliferative phase) progesterone (P4; secretory phase) and estrogen plus progesterone (E2P4; the receptive phase). EV sized particles were isolated by differential centrifugation and size exclusion chromatography. Nanoparticle tracking analysis was used to examine the different concentration and size of particles and EV proteomic analysis per-formed using shotgun label-free mass spectrometry. Our results showed that although endome-trial derived EVs were secreted in numbers independent of hormonal stimulation, EVs sizes were statistically modified by it. Proteomics analysis showed that hormone treatment changes affect the endometrial EVs proteome, with proteins enhanced within the EV E2P4 group shown to be in-volved in different processes such as embryo implantation, endometrial receptivity, and embryo development, supporting the concept of a communication system between the embryo and the maternal endometrium via EVs.
2023-02-13 | PXD039764 | Pride
Project description:The Illumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in endometrium tissues from women with metastatic endometrial cancer. Endometrium tissue samples were drawn from 18 metastatic endometrial cancers. The metastatic endometrial cancer tissue samples were from women (mean age 67.1) who were diagnosed with metastatic endometrial cancer. Bisulphite converted DNA from the 18 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2
2012-02-20 | E-GEOD-33422 | biostudies-arrayexpress
Project description:The Illumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in endometrium tissues from women with metastatic endometrial cancer. Endometrium tissue samples were drawn from 18 metastatic endometrial cancers. The metastatic endometrial cancer tissue samples were from women (mean age 67.1) who were diagnosed with metastatic endometrial cancer.
2012-02-20 | GSE33422 | GEO
Project description:It has been recognised for a long time that cell surface glycans plays a vital role in the biological process and their altered form can lead to cancer. However, the molecular details and regulatory mechanism between the glycans and cancer is yet not clear. Over the past decade mass spectrometry-based techniques has become a prominent method for analysing glycans especially N-glycan matrix assisted laser desorption/ionisation mass spectrometry imaging (MALDI MSI). It is a powerful technique that combines mass spectrometry with histology, enabling the visualisation and label free detection of N-linked glycans on a single tissue section. Here, we carried out N-glycan MALDI MSI on six endometrial cancer (EC) formalin fixed paraffin embedded (FFPE) tissue sections including the adjacent normal endometrium, and tissue microarrays (TMA) consisting of 8 EC patients with lymph node metastasis (LNM) and 20 without LNM. By doing that several m/z values were detected that can significantly distinguish normal endometrium from cancerous. Also, detected a m/z value that can discriminate the primary tumour with LNM from those without. Identification of those discriminative m/z values was performed using porous graphitized carbon liquid chromatography tandem mass spectrometry (PGC-LC-MS/MS). Overall, we observed higher abundance of oligomannose in tumour regions compared to normal with AUC ranges from 0.85-0.99. Whereas, complex N-glycans were detected in lower abundance with AUC ranges from 0.03-0.28. Comparison of N-glycans between the primary tumours with LNM and without LNM indicates reduced abundance of a complex core-fucosylated N-glycan in patients with metastasis relative to without. In summary, N-glycan MALDI MSI can be used to characterize the cancerous endometrium from the normal, also patients with LNM from those without. Identification of those discriminative m/z values was performed using porous graphitized carbon liquid chromatography tandem mass spectrometry (PGC-LC-MS/MS).
2020-11-27 | PXD019425 | Pride
Project description:Gene expression profile of cancerous and non-cancerous renal tissues
| PRJNA714233 | ENA
Project description:DNA methylation profile of cancerous and non-cancerous renal tissues
| PRJNA701825 | ENA