Embryological cellular origins and hypoxia-mediated mechanisms in PIK3CA-driven refractory vascular malformations
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1170937 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30932555_1.fastq.gz | Fastqsanger.gz | |||
| SRR30932555_2.fastq.gz | Fastqsanger.gz | |||
| SRR30932556_1.fastq.gz | Fastqsanger.gz | |||
| SRR30932556_2.fastq.gz | Fastqsanger.gz |
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Project description:Congenital vascular malformations, affecting 0.5% of the population, frequently occur in the head and neck, complicating treatment due to their vital functions. Our previous research identified distinct developmental origins for blood and lymphatic vessels in these regions in both mouse and human embryos. In this study, we expressed Pik3caH1047R in the cardiopharyngeal mesoderm (CPM) to investigate the pathogenesis of these malformations. Mice expressing Pik3caH1047R in the CPM developed abnormal vasculature restricted to the head and neck. Single-cell RNA sequencing revealed that Pik3caH1047R promotes Vegf-a expression in endothelial cells via Hif-driven hypoxia signaling. Human samples corroborated these findings, showing elevated HIF-1α and VEGF-A in malformed vessels. Notably, treatment with Hif-1α and Vegf-a inhibitors significantly reduced abnormal vasculature in the mouse model. Our findings highlight the role of developmental origins and hypoxia-driven mechanisms in vascular malformations, providing a basis for developing targeted therapies for these refractory conditions.
2025-03-12 | GSE279129 | GEO
Project description:Purpose: Cerebral cavernous malformations (CCMs) are hemorrhagic neurovascular malformations that may lead to stroke, seizures and other clinical sequelae. Recent studies have shown that somatic mutations in MAP3K3 and PIK3CA also contribute to CCM pathogenesis; however, it remains unclear how these mutations contribute to sporadic versus familial cases. In our previous research, we’ve shown that co-occurring MAP3K3 and PIK3CA mutations are present within the same clonal population of cells. The overall goal of this study was to identify PIK3CA mutations in CCM-associated developmental venous anomalies (DVA). We also analyzed the plasma miRNome of patients with (1) DVA without associated CCM, as well as (2) DVA with an associated CCM) to identify circulating miRNAs that might serve as biomarkers reflecting PIK3CA activity. Methods: We collected and sequenced the plasma miRNome of 12 individuals with a sporadic CCM associated with a DVA (CCM + DVA), 6 individuals with a DVA without a CCM (DVA only), and 7 healthy controls. Results: We found that the identical PIK3CA mutation is found in endothelial cells of both the DVA and its associated CCM, but that an activating MAP3K3 mutation appears only in the CCM. The analyses miR-134-5p was downregulated in the groups of patients with only a DVA only group (when compared to healthy controls). This miRNA has been shown to target PIK3CA. In addition, miR-182-5p, was upregulated and targets MAP3K3; while let-7c-5p was downregulated and targets both PIK3CA and MAP3K3 in the group of patients with CCM and an associated DVA (when compared to DVA only). Conclusions: These results support a mechanism where DVA develop as the result of a PIK3CA mutation, creating a region of the brain vasculature that functions as a genetic primer for CCM development following acquisition of an additional somatic mutation.
2022-02-06 | GSE195732 | GEO
Project description:Sporadic venous malformations (VM) and angiomatosis of soft tissue (AST) are benign, congenital slow-flow vascular anomalies that have no available targeted therapies. Depending on the size and location of the lesion, symptoms vary from motility disturbances to pain and disfigurement. By analyzing tissue samples from 36 patients with VM or AST, we uncover that the majority of the samples carry a somatic mutation in either TEK or PIK3CA gene. In the current data set, we study the role of PIK3CA point mutation p.H1047R on the transcriptional profile of human umbilical vein endothelial cells (HUVEC-s).
2023-06-10 | GSE196311 | GEO
Project description:Sporadic venous malformations (VM) and angiomatosis of soft tissue (AST) are benign, congenital slow-flow vascular anomalies that have no available targeted therapies. Depending on the size and location of the lesion, symptoms vary from motility disturbances to pain and disfigurement. In this work, we analyzed tissue samples from 36 patients with VM or AST. Additionally, patient-derived endothelialCD31+ and intervascular stromalCD31-, vimentin+ cells were used. Majority of the samples had a somatic mutation in either TEK or PIK3CA gene. Activation of ErbB1/EGFR pathway and expression of a pro-angiogenic ligand, transforming growth factor A, was found in both VM and AST samples. Activation of EGFR pathway led to the secretion of a major angiogenic factor VEGF-A. Intriguingly, patient-derived intervascular stromal cells were able to induce angiogenesis of genotypically normal endothelial cells via paracrine signaling. Significant decrease in endothelial sprouting and VEGF-A production were observed after treatment with a pan-ErbB inhibitor afatinib. To conclude, our data demonstrate that intervascular stromal cells play a role in the pathogenesis of AST and VM by producing pro-angiogenic factors that activate EGFR. Activation of EGFR pathway was not associated with a genetic cause but is likely caused by hypoxia. EGFR targeted therapy of both intervascular stromal cells and endothelial cells could be beneficial for the treatment of a subpopulation of AST and VM lesions expressing EGFR ligands.
2023-01-01 | GSE130807 | GEO
Project description:Human HCC cell lines SNU387 and SNU449 stably transfected (lentivirus) with PIK3CA E545K, PIK3CAH1047R, EGFP or WT. Comparison to determine differential effectors of PIK3CA helical and kinase domain mutants by microarray.
2021-08-29 | GSE182915 | GEO
Project description:Gene targeting was carried out by Taconic Artemis (Cologne, Germany) to introduce a point mutation resulting in conversion of CAT (H) to CGT (R) in the C-terminal p110α kinase domain, and a neo selection cassette flanked by frt sites (publication doi: 10.1038/s41467-017-02002-4). MEFs were made from PIK3CA-H1047R/WT and PIK3CA-WT/WT E13.5 embryos (4 independent MEFs per genotype), treated with 1 μM 4-OHT for one day and gathered 48h after the start of 4-OHT induction were subjected to mRNA sequencing to determine changes in gene expression upon short term PIK3CA activation in the absence of other transforming mutations. PIK3CA-H1047R/WT MEFS exhibited altered expression of 71 genes (q cutoff <0.05).
2019-10-01 | GSE135046 | GEO
Project description:Gene expression microarray analyses of PIK3CA H1047R and E545K induced preneoplastic lesions and tumors compared to age matched controls. Plasmids expressing oncogenic forms of PIK3CA (H1047R or E545K mutants) were delivered to the mouse liver by tail vein hydrodynamic injection combined with Sleeping Beauty–mediated somatic integration (SBT-HTVI). Resulting preneoplastic and neoplastic lesions were subjected to gene expression microarray analysis. The putative PIK3CA target gene Galectin1 (Gal1) was further characterized by in vitro studies. Transfection of either PIK3CA E545K or H1047R mutants via SBT-HTVI was sufficient to induce hepatocellular carcinomas in mice. A stepwise hepatocarcinogenesis from singular pericentral lipid-rich preneoplastic hepatocytes to clusters, expansive preneoplastic lesions, and HCCs was observed. In PIK3CA H1047R injected mice, HCCs were detected in the 12 months injection group, while PIK3CA E545K injections resulted in tumor occurrence as early as 3 months after SB-HTVI. Histologically, a predominant lipid-rich phenotype characterized all tumorigenesis stages, as confirmed by Sudan III staining and electron microscopy. Immunohistochemically, preneoplastic lesions and tumors displayed high levels of the lipid master regulators Fatty acid synthase and Stearoyl-CoA desaturase-1. Gal1 was commonly overexpressed in PIK3CA-driven preneoplastic and neoplastic liver lesions by gene expression microarray analysis compared with age-matched controls.
2021-05-06 | GSE173963 | GEO
Project description:Somatic activating mutations within the PIK3CA gene have been recently detected in sporadic lymphatic and venous malformations, and in vascular malformations (VM) associated to overgrowth syndromes, such as CLOVES and Klippel-Trenaunay syndrome. Although VM are often limited to specific tissue areas and can be well treated, in extended or recurrent lesions novel therapeutic approaches are needed. We generated a mouse model of VM by local expression of PIK3CA-activating mutation in endothelial cells. PIK3CA-driven lesions are characterized by large areas of hemorrhage, hyperplastic vessels, infiltrates of inflammatory cells, and elevated endothelial cell density. Such vascular lesions are ameliorated by administration of dual PI3K/mTOR inhibitor, BEZ235, and mTOR inhibitor, Everolimus. Unexpectedly, the expression of PIK3CA-activating mutations in human endothelial cells results in both increased proliferation rates and senescence. Moreover, active forms of PIK3CA strongly promote the angiogenic sprouting. Treatment with PI3K/mTOR inhibitors restores normal endothelial cell proliferation rate and reduces the amount of senescent cells, whereas treatment with Akt inhibitor is less effective. Our findings reveal that PIK3CA mutations have a key role in the pathogenesis of VM and PIK3CA-driven experimental lesions can be effectively treated by PI3K/mTOR inhibitors.
| S-EPMC5833448 | biostudies-literature
Project description:Mutant PIK3CA and Her2 genes are oncogenic and their co-existence in breast cancer has been well identified. However, the gene targets and cell signalling pathway regulated by mutant PIK3CA, Her2 and both of PIK3CA and Her2 have not been well studied. We established stable cell models through transfecting mutant PIK3CA, Her2 and both mutant PIK3CA and Her2 into MCF10A cells and performed Affymetrix microarray to identify downstream target genes controlled by either mutant PIK3CA, Her2 or both PIK3CA and Her2.
2017-06-01 | GSE99512 | GEO
Project description:Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes1-3. Pik3ca and p53 are the two most frequently mutated genes and are associated with different types of human breast cancers4. The cellular origin and the mechanisms leading to Pik3ca-induced tumour heterogeneity remain unknown. Here, we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and its impact on tumour heterogeneity. Surprisingly, oncogenic Pik3ca-H1047R expression at physiological levels5 in basal cells (BCs) using K5CREERT2 induced the formation of luminal ER+PR+ tumours, while its expression in luminal cells (LCs) using K8CREERT2 gave rise to luminal ER+PR+ tumours or basal-like ER-PR- tumours. Concomitant deletion of p53 and expression of Pik3ca-H1047R accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3ca-H1047R in unipotent BCs gave rise to luminal-like cells, while its expression in unipotent LCs gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that have undergone cell fate transition upon Pik3ca-H1047R expression in unipotent progenitors demonstrate a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures, characteristic of the different cell fate switches that occur upon Pik3ca-H1047R expression in BC and LCs, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3ca-H1047R activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation. Luminal and basal cells, or tumour cells, from mice in which expression of PIK3CA-H1047R and YFP (and in some conditions loss of p53) was targeted in basal cells using K5CREERT2 or in luminal cells using K8CREERT2 were FACS isolated and RNA was extracted before being hybridized Affymetrix microarrays.
2015-08-13 | E-GEOD-69290 | biostudies-arrayexpress