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GDF-15 is a biomarker of aggressiveness and is down-regulated by the mTOR inhibitor sirolimus through ATF4 and ATF5 suppression in epithelioid hemangioendothelioma.

ABSTRACT: GDF-15 is a biomarker of aggressiveness and is down-regulated by the mTOR inhibitor sirolimus through ATF4 and ATF5 suppression in epithelioid hemangioendothelioma.

PROVIDER: PRJNA1032087 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26525700_1.fastq.gz	Fastqsanger.gz
	SRR26525700_2.fastq.gz	Fastqsanger.gz
	SRR26525701_1.fastq.gz	Fastqsanger.gz
	SRR26525701_2.fastq.gz	Fastqsanger.gz
	SRR26525702_1.fastq.gz	Fastqsanger.gz

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GDF-15 is a biomarker of aggressiveness and is down-regulated by the mTOR inhibitor sirolimus through ATF4 and ATF5 suppression in epithelioid hemangioendothelioma.

Project description:Growth and differentiation factor-15 (GDF-15), a member of the TGF-β superfamily, exhibits elevated expression in various tumor types, often linked to disease aggressiveness. In this study, which used patient-derived xenografts and paired cell lines of epithelioid hemangioendothelioma (EHE), it was found that EHE cells produce and release GDF-15. Furthermore, the mTOR inhibitor sirolimus was observed to inhibit GDF-15 expression and release by down-regulating ATF4 and ATF5 transcription factors. To assess the clinical relevance of GDF-15 in EHE, which can manifest as both relatively indolent and exceptionally aggressive forms, circulating GDF-15 levels were assessed in two independent cohorts of EHE patients, one retrospective and one prospective. The results provided evidence of an association between circulating GDF-15 levels and the aggressiveness of EHE. In summary, these findings suggest that GDF-15 can serve as a biomarker for EHE aggressiveness and may have implications for monitoring the effectiveness of sirolimus in EHE patients.

2024-04-24 | GSE246235 | GEO

GDF-15 is a biomarker of aggressiveness and is down-regulated by the mTOR inhibitor sirolimus through ATF4 and ATF5 suppression in epithelioid hemangioendothelioma.

2024-04-24 | GSE246152 | GEO

GDF-15 is a biomarker of aggressiveness and is down-regulated by the mTOR inhibitor sirolimus through ATF4 and ATF5 suppression in epithelioid hemangioendothelioma.

Project description:GDF-15 is a biomarker of aggressiveness and is down-regulated by the mTOR inhibitor sirolimus through ATF4 and ATF5 suppression in epithelioid hemangioendothelioma.

| PRJNA1031665 | ENA

GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression.

Project description:PurposeEpithelioid hemangioendothelioma (EHE), an ultra-rare sarcoma, poses therapeutic challenges because of limited efficacy of conventional chemotherapy in advanced cases, necessitating exploration of new treatment avenues and identification of novel aggressive biomarkers. This study aimed at (i) utilizing a patient-derived xenograft model of EHE and its associated cell line to assess the efficacy of sirolimus and (ii) analyzing two distinct patient cohorts to pinpoint circulating biomarkers of EHE aggressiveness.Experimental designA patient-derived xenograft model and corresponding cell line were established from a patient with advanced EHE, demonstrating consistency with the original tumor in terms of histomorphology, WWTR1::CAMTA1 fusion presence, and genomic and transcriptomic profiles. Two independent patient series were employed to investigate the association between growth/differentiation factor 15 (GDF-15) serum levels and EHE aggressiveness.ResultsELISA analyses on EHE cell culture medium and blood from EHE-carrying mice revealed the release of GDF-15 by EHE cells. Sirolimus exhibited markedly higher antitumor activity compared with doxorubicin, concurrently reducing GDF-15 expression/release both in vivo and in vitro. This reduction was attributed to the drug-induced inhibition of phosphorylation/activation of 4E-BP1 and subsequent downregulation of the GDF-15 transcription factors ATF4 and ATF5. Blood sample analyses from two independent patient series showed a significant correlation between GDF-15 and EHE aggressiveness.ConclusionsThis study identifies GDF-15 as a novel biomarker of EHE aggressiveness and underscores the superior efficacy of sirolimus compared with doxorubicin in our experimental models. The observed inhibition of GDF-15 release by sirolimus suggests its potential as a biomarker for monitoring the drug's activity in patients.

| S-EPMC11565171 | biostudies-literature

RNA-Seq of Human Epithelioid Hemangioendothelioma

Project description:RNA-Seq of Human Epithelioid Hemangioendothelioma

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RNA-Seq of Epithelioid Hemangioendothelioma cell lines

Project description:Epithelioid hemangioendothelioma (EHE) is a rare vascular sarcoma that is associated with a WWTR1-CAMTA1 fusion gene in greater than 90% of cases. Cell lines were generated from WWTR1-CAMTA1 positive murine EHE tumors which also harbor a loss of CDKN2A. RNA sequencing was performed on cell lines.

2022-12-16 | GSE220539 | GEO

RNA-Seq of Human Epithelioid Hemangioendothelioma

Project description:Epithelioid hemangioendothelioma (EHE) is a rare vascular sarcoma that is associated with a WWTR1-CAMTA1 fusion gene in greater than 90% of cases. We aimed to investigate the transcriptional pathways activated in EHE. Total RNA was isolated from EHE tumors from surgical resection or autopsy specimens (n=6) followed by RNA-Seq. The results of this study identified a unique transcriptional profile for EHE and helped to validate a novel murine model of EHE.

2021-03-25 | GSE168493 | GEO

RNA-Seq of Epithelioid Hemangioendothelioma cell lines

Project description:RNA-Seq of Epithelioid Hemangioendothelioma cell lines

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scRNA-Seq of Cdkn2a mutant murine Epithelioid Hemangioendothelioma tumors

Project description:Epithelioid hemangioendothelioma (EHE) is a rare vascular sarcoma that is associated with a TAZ-CAMTA1 fusion in greater than 90% of cases and loss of CDKN2A in human EHE tumors is associated with late stage disease. Murine EHE tumors were created by conditionally expressing TAZ-CAMTA1 and conditionally knocking out Cdkn2a within vascular endothelium. Resultant tumors were used for single cell RNA sequencing and compared against age matched wild type mice tissue.

2022-12-16 | GSE220540 | GEO

scRNA-Seq of genetically engineered mouse model of Epithelioid Hemangioendothelioma tumors

Project description:Epithelioid hemangioendothelioma (EHE) is a rare vascular sarcoma that is associated with a WWTR1-CAMTA1 fusion gene in greater than 90% of cases. Using an adaptation of the FLEx system, we generated a genetically engineered mouse model of EHE whereby the endogenous Wwtr1 Locus is replaced with an Wwtr1-Camta1 locus. Tumors generated from this mouse model were dissociated and a 10X genomics library preparation was performed. The barcoded library was then deep sequenced.

2021-03-25 | GSE168354 | GEO

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