RNA profiling of MPNST xenografts treated with anti-endoglin (ENG) therapies
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE219148 | GEO | 2023/07/21
REPOSITORIES: GEO
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Project description:In order to study the gene expression changes related to ENG silencing in MPNST cells, we performed RNA-seq gene expression profiling after knockdown of ENG in STS26T cells compared to shScramble control.
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Project description:Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma that lacks effective therapeutic strategies. By characterizing recurrent gene copy number aberrations, we gain insight into the most altered pathways with the purpose of scanning possible therapeutic targets. We conducted a microarray-based comparative genomic hybridization profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center and 26 patients from Tianjin Cancer Hospital. All samples had at least 90% tumor content. Commercially available normal genomic DNAs were used as control.
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Project description:Patients with a heterozygous mutation in Endoglin (Eng) suffer from hereditary hemorrhagic telangiectasia (HHT), a condition characterized by the development of arteriovenous malformations (AVMs) across various organs, leading to significant bleeding, blood abnormalities, and anemia. Eng is a transmembrane protein and an accessory receptor for transforming growth factor-β (TGF-β) and is therefore essential for maintaining normal vascular architecture. Despite extensive research linking Eng deficiency to AVMs, the precise mechanisms driving this association remain poorly understood. In addition, the role of the bone marrow, a primary source of immune and other blood cells, in the context of endothelial Eng (EC-Eng) deficiency has yet to be explored. In this study, we demonstrate that bone marrow blood vessels conditionally deficient in Eng undergo a temporally orchestrated remodeling process over four weeks, characterized by distinct proliferative and resolution phases. We detail the specific phases of this remodeling, including angiogenic set points, the involvement of the beta integrin family, and modulation of vascular integrity. Furthermore, we explore the impact on the hematopoietic stem and progenitor cell (HSPC) compartment and the resultant changes in circulating blood cells. Using a conditional heterozygous deficient EC-Eng mouse model, we observe significant similarities to phenotypes described in the cKO line, which may ultimately be detrimental in patients with HHT. Taken together, using a combination of different in vivo approaches, our research proposes that very low levels of Eng expression in the endothelium may drive critical vascular remodeling in the bone marrow, sharing mechanisms with early vascular processes leading to AVM formation.
2024-07-25 | GSE271409 | GEO
Project description:Much remains unknown about the signals that induce early mesoderm to initiate hematopoietic differentiation. Here we show that endoglin (Eng), a receptor for the TGFβ superfamily, identifies all cells with hematopoietic fate in the early embryo. These arise in an Eng+Flk1+ mesodermal precursor population at E7.5, a cell fraction also endowed with endothelial potential. In Eng knockout embryos, hematopoietic colony activity and numbers of CD71+Ter119+ erythroid progenitors were severely reduced. This coincided with severely reduced expression of embryonic globin and key BMP target genes including the hematopoietic regulators Scl, Gata1, Gata2 and Msx-1. To interrogate molecular pathways active in the earliest hematopoietic progenitors, we applied transcriptional profiling to sorted cells from E7.5 embryos. Eng+Flk-1+ progenitors co-expressed TGFβ and BMP receptors and target genes. Furthermore, Eng+Flk-1+ cells presented high levels of phospho-SMAD1/5, indicating active TGFβ and/or BMP signaling. Remarkably, under hematopoietic serum-free culture conditions, hematopoietic outgrowth of endoglin-expressing cells was dependent on TGFβ superfamily ligands: BMP4, BMP2, or TGF-β1. These data demonstrate that the E+F+ fraction at E7.5 represents mesodermal cells competent to respond to TGFb1, BMP4, or BMP2, shaping their hematopoietic development, and that endoglin is a critical regulator in this process by modulating TGF/BMP signaling. E7.5 pooled embryos (25 litters; 300 embryos approximately) were dissected and 3,000 cells were sorted in triplicate for Eng-Flk1-, Eng-Flk1+, Eng+Flk1+, and Eng+Flk1- fractions. Microarray results were analyzed with GeneSpring GX software.
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Project description:We utilized three murine MPNST cell lines. 67C-4 and #5NPCIS cell lines are derived from spontaneously arising tumors in mice mutated for NF1 and p53 (so-called NP-cis mice; PMID: 12154062). SN4-4 cells originated from MPNST tumors induced by injecting adenovirus containing Cas9 and guide RNA for Nf1 and p53 into the sciatic nerves, resulting in NF1/p53-null MPNST (PMID: 32456131). We implanted 5 x 10^6 murine MPNST cells, subcutaneously, into the flanks of 6-8 weeks old gender-matched C57BL/6 mice (for 67C-4 and #5NPCIS) and BALB/c mice (for SN4-4 mice) to generate MPNST tumors. All mice were procured from Envigo. Upon reaching a size of 300-500 mm3, the mice were euthanized to harvest the tumors, which were subsequently flash frozen using liquid nitrogen and processed for RNA sequencing.
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Project description:The diagnosis of Malignant peripheral nerve sheath tumors (MPNSTs) can be challenging, but is aided by their characteristic DNA methylation profile (DMP). An MPNST-like group, characterized by retained H3K27me3 expression, was recently recognized. To evaluate the diagnostic usefulness of DMP in pediatric/juvenile MPNSTs, we selected pediatric/juvenile malignancies from the Bambino Gesù Children's Hospital DMP database. DMP revealed unexpected molecular heterogeneity in histologically homogenous MPNSTs/Atypical neurofibromas, while samples with MPNST-like DMP manifested histological diversity. In conclusion, DMP is useful in diagnosing MPNST, discriminating morphologic mimics classified as MPNST in premolecular era, and investigating the MPNST-like ‘hybrid’ group in pediatrics.
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Project description:Comprehensive transcriptomic profiling of PRC2 mutant MPNST patient tissues with adjacent normal tissues and neurofibroma patient tissues was performed to investigate gain of specific transcriptional signature associated with PRC2 loss during transformation to MPNST.
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Project description:In order to comprehensively define the epigenetic patterns specific to MPNST, we generated profiles for 6 histone modification marks, including H3K4me1 (enhancer), H3K27Ac (active enhancer), H3K9me3 (heterochromatin), H3K27me3 (polycomb repression), H3K79me2 (transcription) and H3K4me3 (promoter). Systematic epigenomic profiling of chromatin states in MPNST cells revealed epigenetic subtypes in MPNST based on Polycomb related repressive and bivalent chromatin states. We demonstrate that PRC2 loss led to de-repression and subsequent enhancer reprogramming at key neural crest specifiers aiding the acquisition of this de-differentiated aggressive tumor phenotype.
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Project description:Comparison of copy number changes in MPNST samples against benign neurofibromas in NF1 patients 24 MPNSTs and 3 NF samples were hybridised to the human 32K BAC tiling path array
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Project description:We used single-cell RNAseq to profile early and advanced mouse MPNST tumors, as well as human neurofibroma and MPNST. Our work defines the stage-specific kinetics of transcriptomics, cellular heterogeneity, and tumor cell fate decisions in murine and human MPNSTs.
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