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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: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246235 | GEO | 2024/04/24

REPOSITORIES: GEO

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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 | GSE246152 | 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

A Growth Factor-Expressing Macrophage subpopulation orchestrates regenerative inflammation via GDF-15

Project description:Muscle regeneration is the result of the concerted action of multiple cell types driven by the temporarily controlled phenotype switches of infiltrating monocyte-derived macrophages. Proinflammatory macrophages transition into a phenotype that drives tissue repair through the production of effectors such as growth factors. This orchestrated sequence of regenerative inflammatory events, which we termed Regeneration-Promoting Program (RPP), is essential for proper repair. However, it is not well understood how specialized repair-macrophage identity develops in the RPP at the transcriptional level and how induced macrophage-derived factors coordinate tissue repair. Gene expression kinetics-based clustering of blood circulating Ly6Chigh, infiltrating inflammatory Ly6Chigh, and reparative Ly6Clow macrophages, isolated from injured muscle, identified the TGF-beta superfamily member, GDF-15, as a component of the RPP. Myeloid GDF-15 is required for proper muscle regeneration following acute sterile injury, as revealed by gain- and loss-of-function studies. Mechanistically, GDF-15 acts both on proliferating myoblasts and muscle-infiltrating myeloid cells. Epigenomic analyses of upstream regulators of Gdf15 expression identified that it is under the control of nuclear receptors RXR/PPARg. Finally, immune single-cell RNA-seq profiling revealed that Gdf15 is coexpressed with other known muscle regeneration-associated growth factors, and their expression is limited to a unique subpopulation of repair-type macrophages (Growth Factor-Expressing Macrophages, GFEM).

2021-10-27 | GSE164722 | GEO

A Growth Factor-Expressing Macrophage subpopulation orchestrates regenerative inflammation via GDF-15

2021-11-16 | GSE182455 | GEO

A Growth Factor-Expressing Macrophage subpopulation orchestrates regenerative inflammation via GDF-15 [scRNA-seq]

Project description:Muscle regeneration is the result of the concerted action of multiple cell types driven by the temporarily controlled phenotype switches of infiltrating monocyte-derived macrophages. Proinflammatory macrophages transition into a phenotype that drives tissue repair through the production of effectors such as growth factors. This orchestrated sequence of regenerative inflammatory events, which we termed Regeneration-Promoting Program (RPP), is essential for proper repair. However, it is not well understood how specialized repair-macrophage identity develops in the RPP at the transcriptional level and how induced macrophage-derived factors coordinate tissue repair. Gene expression kinetics-based clustering of blood circulating Ly6Chigh, infiltrating inflammatory Ly6Chigh, and reparative Ly6Clow macrophages, isolated from injured muscle, identified the TGF-beta superfamily member, GDF-15, as a component of the RPP. Myeloid GDF-15 is required for proper muscle regeneration following acute sterile injury, as revealed by gain- and loss-of-function studies. Mechanistically, GDF-15 acts both on proliferating myoblasts and muscle-infiltrating myeloid cells. Epigenomic analyses of upstream regulators of Gdf15 expression identified that it is under the control of nuclear receptors RXR/PPARg. Finally, immune single-cell RNA-seq profiling revealed that Gdf15 is co-expressed with other known muscle regeneration-associated growth factors, and their expression is limited to a unique subpopulation of repair-type macrophages (Growth Factor-Expressing Macrophages, GFEM).

2021-11-03 | GSE161467 | GEO

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

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

RNA-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. RNA was isolated from the resultant tumors and from control liver tissue and RNA sequencing was performed. Cross species analysis between human and mice tumors demonstrated murine EHE maintains the defining transcriptional features of human EHE.

2021-03-25 | GSE168494 | GEO

Study of the Efficacy and Safety of Ponsegromab in Patients With Cancer, Cachexia and Elevated GDF-15

Project description:Study to evaluate the efficacy, safety and tolerability of ponsegromab compared to placebo in patients with cancer, cachexia, and elevated GDF 15.

| 2748827 | ecrin-mdr-crc

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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