A multiplexing strategy to create primary and orthotopic endometrial cancer models in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE203121 | GEO | 2023/05/16
REPOSITORIES: GEO
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Project description:<p>Endometrial diseases are common gynecological diseases that disorder women of childbearing age and perimenopausal women, including endometrial polyps (EP), endometrial cancer (EC), and endometrial hyperplasia (EH). Clinically, biopsy or imaging methods are usually used to screen and diagnose endometrial diseases, but due to their invasiveness and heterogeneity, a noninvasive, convenient, objective and accurate biomarker is needed for the differential diagnosis of EP and EC or EH. In the present study, serum samples from 396 patients with endometrial disease and 225 healthy volunteers were analyzed by UPLC-Q-TOF/MS non-targeted lipidomics. A combination of multivariate (Orthogonal partial least-squares discriminant analysis) and univariate (Student t-test) analyses were used to identify and qualify 6, 8, and 7 potential biomarkers in serum from patients with EP, EC, and EH, respectively. With the aid of logistic regression algorithm and receiver operating characteristic (ROC) curve analysis, A biomarker panel including four specific EP biomarkers, 6-Keto-PGF1α, PA(37:4), LysoPC(20:1) and PS (36:0), had good classification and diagnostic ability in distinguishing EP from EC or EH. The biomarker panel can be used as a rapid diagnostic method to assist imaging examination to effectively differentially diagnose endometrial diseases, and provide a reference for clinicians in the identification and diagnosis of endometrial diseases. </p>
2022-01-14 | MTBLS3444 | MetaboLights
Project description:Endometrial cancer is the most common gynecological cancer worldwide. In women from developed countries, endometrial cancer is usually detected after the age of 60 years. Nearly 90% of the diagnosed cases are sporadic, while 10% are attributed to genetic factors. Thus, it is necessary to develop a diagnostic platform. Currently, the lymph node status is a major prognostic factor in assessing endometrial cancer. However, despite its high sensitivity, it is still in debate. In order to increase its selectivity and specificity, in-depth proteomic study has been performed on patients sentinel lymph node (SNL) samples and on grade I to grade III endometrial carcinoma (EC) samples. We identified specific markers of bad diagnosis that clearly correlate SNL to EC i.e. PRSS3, PTX3, ASS1, YBX2, RBM25, MUC5B. These markers have also been detected in TCGA. By contrast, we also detected good prognosis markers for the overall survival such as CD74, GOLM1, SLC9A3R2, SP100 proteins. Markers for EC and SNL cancer-grading have also been identified. Taken together, it is now possible to propose a novel approach for molecular diagnosis, prognosis and patient’s stratification in EC which will be of excellent utility in therapeutic decision.
2021-09-09 | PXD020410 | Pride
Project description:Endometrial cancer (EC) is one of the most common gynecological cancers. Finding biomarkers of EC can support its diagnosis in a non- or minimally-invasive way. In this work, we integrated metabolomics and proteomics for the analysis of multiple types of biosamples to gain a more comprehensive view on the altered metabolism in EC patients, and to demonstrate the potential of metabolite biomarker-based EC diagnosis. Based on the differential metabolites and proteins between EC patients and controls detected in the endometrial tissue samples, EC related significant pathways, such as amino acid metabolism and nucleotide metabolism, were identified. Then, the significance of the pathways was further demonstrated by metabolomic analysis of urine and intrauterine brushings samples. We also demonstrated the potential of EC diagnosis by metabolite biomarkers in urine or intrauterine brushings samples. This study provides a network explanation of the metabolic changes of EC with the verification by multi-omics and multi-biosamples, and further demonstrates the potential of non- or minimally-invasive biopsy for EC diagnosis in the future.
2022-03-28 | MTBLS3935 | MetaboLights
Project description:Most endometrial cancers are driven by excess estrogen signaling and express the hormone receptor estrogen receptor alpha (ER). Evaluation of the estrogen response in endometrial cancer cells has been limited by the availability of hormonally responsive in vitro models, with one cell line, Ishikawa, being used in most studies. Here, we describe a novel, adherent endometrioid endometrial cancer (EEC) cell line model, HCI-EC-23. We show that HCI-EC-23 retains ER expression and that ER functionally responds to 17b-estradiol (E2) induction over a range of passages. We also demonstrate that this cell line retains paradoxical activation of ER by tamoxifen, which is also observed in Ishikawa and is consistent with clinical data. The mutational landscape shows that HCI-EC-23 is mutated at many of the commonly altered genes in EEC, has relatively few copy-number alterations, and is microsatellite instable high (MSI-high). In vitro proliferation of HCI-EC-23 is modestly enhanced by E2 but is strongly reduced upon combination E2 and progesterone (P4) treatment. HCI-EC-23 exhibit strong E2 dependence for tumor growth in vivo and tumor size is reduced by combination E2 + P4 treatment. Molecular characterization of E2 induction in HCI-EC-23 revealed hundreds of estrogen-responsive genes that significantly overlapped with those regulated in Ishikawa. Analysis of ER genome binding identified similar patterns in HCI-EC-23 and Ishikawa, although ER exhibited more bound sites in Ishikawa. This study demonstrates that HCI-EC-23 is estrogen-responsive and can be used to study the hormonal aspects of endometrial cancer.
2022-08-02 | GSE210123 | GEO
Project description:Most endometrial cancers are driven by excess estrogen signaling and express the hormone receptor estrogen receptor alpha (ER). Evaluation of the estrogen response in endometrial cancer cells has been limited by the availability of hormonally responsive in vitro models, with one cell line, Ishikawa, being used in most studies. Here, we describe a novel, adherent endometrioid endometrial cancer (EEC) cell line model, HCI-EC-23. We show that HCI-EC-23 retains ER expression and that ER functionally responds to 17b-estradiol (E2) induction over a range of passages. We also demonstrate that this cell line retains paradoxical activation of ER by tamoxifen, which is also observed in Ishikawa and is consistent with clinical data. The mutational landscape shows that HCI-EC-23 is mutated at many of the commonly altered genes in EEC, has relatively few copy-number alterations, and is microsatellite instable high (MSI-high). In vitro proliferation of HCI-EC-23 is modestly enhanced by E2 but is strongly reduced upon combination E2 and progesterone (P4) treatment. HCI-EC-23 exhibit strong E2 dependence for tumor growth in vivo and tumor size is reduced by combination E2 + P4 treatment. Molecular characterization of E2 induction in HCI-EC-23 revealed hundreds of estrogen-responsive genes that significantly overlapped with those regulated in Ishikawa. Analysis of ER genome binding identified similar patterns in HCI-EC-23 and Ishikawa, although ER exhibited more bound sites in Ishikawa. This study demonstrates that HCI-EC-23 is estrogen-responsive and can be used to study the hormonal aspects of endometrial cancer.
2022-08-02 | GSE210122 | GEO
Project description:The gut-uterus axis plays a pivotal role in the pathogenesis of endometrial cancer (EC). However, the correlations between the endometrial microbiome and endometrial tumor transcriptome in patients with EC and the impact of the endometrial microbiota on hematological indicators have not been thoroughly clarified. In this prospective study, endometrial tissue samples collected from EC patients (n = 30) and healthy volunteers (n = 10) were subjected to 16S rRNA sequencing of the microbiome. The 30 paired tumor and adjacent nontumor endometrial tissues from the EC group were subjected to RNAseq. Result: We found that Pelomonas and Prevotella were enriched in the EC group with a high tumor burden. Further transcriptome analysis identified 8 robust associations between Prevotella and fibrin degradation-related genes expressed within ECs. Conclusions: Our results suggest that the increasing abundance of Prevotella in endometrial tissue combined with high serum DD and FDP contents may be important factors associated with tumor burden.
2021-10-13 | GSE183185 | GEO
Project description:A specific form of endometrial cancer (EC) can develop in breast cancer patients previously treated with tamoxifen (ET), an antagonist of estrogen receptor (ER) α that inhibits proliferation of ER positive breast cancer. ET tumors have a different phenotype than endometrial tumors which typically develop de novo without previous exposure to tamoxifen (EN). Here we aimed to identify specific protein markers that could serve as specific molecular targets in either phenotype. A set of total 45 formalin-fixed paraffin-embedded (FFPE) endometrial tumor tissue and adjacent myometrial tissue samples were analyzed using LC-MS/MS in SWATH-MS mode. We found that calcyphosin (CAPS) levels were elevated in EN tumors compared to ET tumors. The higher CAPS level in EC tissue invading to myometrium support its relationship to EC aggressiveness. Further, stathmin (STMN1) levels were found significantly elevated in ET vs. EN tumors and significantly associated with patient survival. This finding connects elevated levels of this cell cycle regulating, proliferation-associated protein with tamoxifen exposure. In a summary, using SWATH-MS we show that CAPS and STMN1 should be recognized as clinicopathologically different EC markers of which STMN1 is specifically connected with a previous tamoxifen exposition.
2020-05-05 | PXD017217 | Pride
Project description:Progestins are commonly used as the conservative endocrine treatment of young early endometrial cancer (EC) patients. Circular RNAs (circRNAs) are new group players in multiple cellular functions. This study aims to identify the differentially expressed circular RNAs (DE-circRNAs) in endometrial cancer (EC) cells upon the progesterone treatment. aiding in the understanding of the impact of circRNAs in pregestin therapy.
2021-07-22 | GSE180424 | GEO
Project description:Endometrial cancer (EC) incidence and mortality continues to rise. Molecular profiling of EC promises improvement of risk assessment and treatment selection. Though, we still lack robust and accurate models to predict those at risk of failing treatment. The objective of this pilot study is to create models with clinical and genomic data that will discriminate patients with EC at risk of disease recurrence. We performed a pilot, retrospective, case-control study evaluating patients with EC, endometrioid type: 7 with recurrence of disease (cases), and 54 without (controls). RNA was extracted from frozen specimens and sequenced (RNAseq). Genomic features from RNAseq included transcriptome expression, genomic, and structural variation. Feature selection for variable reduction was performed with univariate ANOVA with cross-validation. Selected variables, informative for EC recurrence, were introduced in multivariate lasso regression models. Validation of models was performed in machine learning platforms (ML) and independent datasets (TCGA). The best performing prediction models (out of >170) contained the same lncRNA features (AUC of 0.9, and 95% CI: 0.75, 1.0). Models were validated with excellent performance in ML platforms and good performance in an independent dataset. Prediction models of EC recurrence containing lncRNA features have better performance than models with clinical data alone
2022-11-02 | GSE216872 | GEO
Project description:Optimization of CRISPR/Cas9-mediated genome engineering has resulted in base editors that hold promise for mutation repair and disease modeling. Here, we demonstrate the application of base editors for the generation of complex tumor models in human ASC-derived organoids. First we show Efficacy of cytosine and adenine base editors in modelingCTNNB1hot-spot mutations in hepatocyte organoids. Next, we use C>T base editors to insert nonsense mutations inPTENin endometrial organoids and demonstrate tumorigenicity even in the heterozygous state. Moreover, drug screening assays on organoids harboring eitherPTENorPTENandPIK3CAmutations reveal the mechanism underlying the initial stages of endometrial tumorigenesis. To further increase the scope of base editing we combine SpCas9 and SaCas9 for simultaneous C>T and A>G editing at individual target sites. Finally, we show that base editor multiplexing allow modeling of colorectal tumorigenesis in a single step by simultaneously transfecting sgRNAs targeting five cancer genes.
2023-07-30 | GSE236490 | GEO