P4HA1 mediates hypoxia-induced invasion in human pancreatic cancer organoids
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PROVIDER: PRJNA1232238 | ENA |
REPOSITORIES: ENA
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Project description:P4HA1 mediates hypoxia-induced invasion in human pancreatic cancer organoids
| PRJNA1232239 | ENA
Project description:Activating transcription factors (ATFs), members of the adaptive-response gene family, participate in cellular processes to aid adaptations in response to extra- and/or intracellular changes. In this study, we observed that one of the ATFs Activating transcription factor 3 (ATF3) is upregulated under hypoxia via alterations in the epigenetic landscape of its promoter, followed by transcriptional upregulation. Under hypoxic conditions, Hypoxia-inducible factor 1-alpha (HIF1ɑ) alleviates methylation at the ATF3 promoter by recruiting TET1 and induces ATF3 transcription. Additionally, our RNA-seq analysis showed that ATF3 globally affects transcription under hypoxia and controls the processes of EMT and cancer invasion by stimulating the transcription of Prolyl 4-Hydroxylase Subunit Alpha 1 (P4HA1), an enzyme which enhances invasion conducive extracellular matrix (ECM) under hypoxic condition. Prolyl hydroxylases play a critical role in the hydroxylation and deposition of collagen in the extracellular matrix (ECM) during the evolution of cancer, which is necessary for metastasis. Importantly, P4HA1 undergoes alternative splicing under hypoxia, where the inclusion of exon 9a is increased. It is interesting to note that ATF3's involvement in P4HA1 splicing was also evident, as binding of ATF3 at intron 9a led to demethylation of this DNA region via recruitment of TET1. Further, we also show that the demethylated DNA region of intron 9a then becomes accessible to CTCF. Thus, a cascade of demethylation via ATF3 recruited TET1, followed by increased RNA PolII pause via CTCF at the intron 9a leads to inclusion of exon 9a. The P4HA1 9a isoform leads to enhanced invasion under hypoxic conditions by increasing deposition of collagen in the ECM. These results provide a novel hypoxia-induced HIF1ɑ-ATF3-P4HA1 axis which can be potentially exploited as a therapeutic target to impede EMT and ultimately breast cancer invasion.
2024-12-31 | GSE274936 | GEO
Project description:Recent studies including next-generation sequencing have identified genomic events in prostate cancer including ETS gene fusions. However, it is critical to identify druggable targets for prostate cancer and their mechanism of action for therapeutic intervention. Here, we show that prolyl 4-hydroxylase, alpha polypeptide I (P4HA1) is overexpressed in aggressive prostate cancer and amplified in a subset of metastatic prostate cancer. This study provides mechanistic insights of P4HA1 regulation and its mode of action including its role in regulating MMP1. Importantly, P4HA1 mediated invasion in cancer cells could be reversed using MMP1 inhibitor, revealing therapeutic utility of targeting P4HA1 either directly or by inhibiting its downstream effectors. Two-color experiment, in duplicates.
2015-05-10 | E-GEOD-55787 | biostudies-arrayexpress
Project description:Recent studies including next-generation sequencing have identified genomic events in prostate cancer including ETS gene fusions. However, it is critical to identify druggable targets for prostate cancer and their mechanism of action for therapeutic intervention. Here, we show that prolyl 4-hydroxylase, alpha polypeptide I (P4HA1) is overexpressed in aggressive prostate cancer and amplified in a subset of metastatic prostate cancer. This study provides mechanistic insights of P4HA1 regulation and its mode of action including its role in regulating MMP1. Importantly, P4HA1 mediated invasion in cancer cells could be reversed using MMP1 inhibitor, revealing therapeutic utility of targeting P4HA1 either directly or by inhibiting its downstream effectors.
2015-05-10 | GSE55787 | GEO
Project description:Placentation requires the proper regulation of extravillous trophoblast (EVT) migration and invasion into the decidua and maternal vasculature, processes which are initiated in physiologic hypoxic conditions. Abnormal EVT migration and/or invasion have been suggested to lead to pregnancy complications, such as preeclampsia. The objectives of this study are to determine how exposure to hypoxia impacts gene expression and cellular motility of first trimester trophoblasts, and to assess if expression of migration-associated genes is dysregulated in 2nd trimester chorionic villous samples (CVS) from preeclampsia pregnancies relative to CVS from healthy pregnancies. The 1st trimester trophoblast cell line, HTR8/SVneo, was used to investigate the relationship between hypoxia and Notch signaling in trophoblast migration and invasion. RNA sequencing and quantitative RT-PCR analyses show that exposure to hypoxia (2.5% O2) activates Notch signaling in HTR-8/SVneo. We demonstrate that exposure of HTR-8/SVneo to hypoxia induces expression of genes associated with cellular migration and invasion and increases HTR-8/SVneo cellular migration and invasion, whereas inhibition of gamma-secretase decreases Notch signaling and decreases HTR-8/SVneo migration and invasion. Analysis of RNA sequencing data from CVS of preeclampsia and uncomplicated pregnancies identified significant differentially expressed genes that are involved in cellular migration and invasion. Decreased expression of migration and invasion genes in CVS from preeclampsia pregnancies, may impair trophoblast migration and invasion in the 2nd trimester of pregnancy, resulting in the development of preeclampsia.
2021-08-05 | GSE155750 | GEO
Project description:To study the differences in gene expression between PDAC organoids grown either as monocultures or co-cultures with panctreatic stellate cells in normoxia and hypoxia.
2023-01-11 | GSE222482 | GEO
Project description:In this study we analyzed impact of long-term hypoxia on a panel of lymphoma cell lines. Only 2 out of 8 tested lymphoma cell lines (Ramos, and HBL2) survived > 4 weeks under deep hypoxia (1% O2). The hypoxia-adapted (HA) Ramos and HBL2 cells had severely decreased proliferation rate accompanied by complex changes of the transcriptome, proteome, and metabolome. Seahorse analysis demonstrated near complete blockage of both oxidative phosphorylation and glycolytic pathways. Both transcriptome and proteome analyses showed significant downregulation of mitochondrial respiration complexes I and IV, many mitochondrial ribosomal proteins, and increase of proteins regulating glycolysis and mitophagy. Both HA cell lines had an increased total mitochondrial mass, but a decreased mitochondrial DNA content compared to normoxic controls. Sensitivity of HA cells to 2-deoxyglucose, an inhibitor of glycolysis, and to A1155463, a BCL-XL inhibitor were, was markedly increased. Indeed, co-culture on CD40 ligand expressing fibroblasts (that induce BCL-XL expression) significantly increased survival of lymphoma cells under hypoxia. Of note, prolyl hydroxylase P4HA1 involved in the stabilization of hypoxia-induced factor (HIF) 1 alpha was increased in both HA cell lines on both mRNA and protein levels. Transgenic (over)expression of P4HA1 in hypoxia-sensitive MINO cells was associated with increased survival under hypoxia. Our data suggest that under long-term hypoxia, lymphoma cells try to compensate for the decrease in ATP production from the oxidative phosphorylation process by boosting structural machinery of glycolysis, as well as amino-acid recycling by mitophagy, on which they become vitally dependent for survival, and which can be targeted by specific inhibitors. The data also suggest increased dependence of lymphoma cells on BCL-XL under hypoxia. Finally, P4HA1 plausibly represents a novel druggable target for more effective elimination of hypoxia-adapted lymphoma cells.
2025-07-01 | GSE266442 | GEO
Project description:Lymphangioleiomyomatosis (LAM) is a debilitating, progressive lung disease with few therapeutic options, largely due to a paucity of mechanistic knowledge of disease pathogenesis. Lymphatic endothelial cells (LECs) are known to envelope and invade clusters of LAM-cells, comprising of smooth muscle α-actin and/or HMB-45 positive "smooth muscle-like cells” however the role of LECs in LAM pathogenesis is still unknown. To address this critical knowledge gap, we investigated wether LECs interact with LAM-cells to augment their metastatic behaviour of LAM-cells. We performed in situ spatialomics and identified a core of transcriptomically related cells within the LAM nodules. Pathway analysis highlights wound and pulmonary healing, VEGF signaling, extracellular matrix/actin cytoskeletal regulating and the HOTAIR regulatory pathway enriched in the LAM Core cells. We developed an organoid co-culture model combining primary LAM-cells with LECs and applied this to evaluate invasion, migration, and the impact of Sorafenib, a multi-kinase inhibitor. LAM-LEC organoids had significantly higher extracellular matrix invasion, decreased solidity and a greater perimeter, reflecting increased invasion compared to non-LAM control smooth muscle cells. Sorafenib significantly inhibited this invasion in both LAM spheroids and LAM-LEC organoids compared to their respective controls. We identified TGFβ1ι1, a molecular adapter coordinating protein-protein interactions at the focal adhesion complex and known to regulate VEGF, TGFβ and Wnt signalling, as a Sorafenib-regulated kinase in LAM-cells. In conclusion we have developed a novel 3D co-culture LAM model and have demonstrated the effectiveness of Sorafenib to inhibit LAM-cell invasion, identifying new avenues for therapeutic intervention.
2024-06-13 | GSE234885 | GEO
Project description:Sorafenib inhibits invasion of multicellular organoids that mimic Lymphangioleiomyomatosis nodules.
| PRJNA983678 | ENA
Project description:Uncontrolled accumulation of pulmonary artery smooth muscle cells (PASMC) to the non-muscularized distal pulmonary arterioles (PAs) is one of the major characteristics of pulmonary hypertension (PH). Cellular senescence contributes to aging and lung diseases associated with PH and links to PH progression. However, the mechanism by which cellular senescence controls vascular remodeling in PH is not fully understood. Here, we have demonstrated that endothelial senescence mediates PH pathology by increasing platelet-derived growth factor (PDGFB) expression. The levels of senescence markers p16INK4A and senescence-associated β-galactosidase (SA-β-gal) are higher in PA endothelial cells (ECs) isolated from IPAH patients compared to those from healthy individuals. Hypoxia-induced accumulation of α-smooth muscle actin (αSMA)-positive cells to the PAs is attenuated in p16INK4Afl/fl-Cdh5(PAC)-CreERT2 mice after tamoxifen induction. We have reported that endothelial TWIST1 mediates hypoxia-induced vascular remodeling by increasing PDGFB expression. Transcriptomic analyses of idiopathic pulmonary arterial hypertension (IPAH) patient lung ECs or hypoxia-induced mouse lung ECs reveal the alteration of senescence-related gene expression and interaction with TWIST1. Increases in the levels of PDGFB and TWIST1 in hypoxia-treated mouse lung ECs or IPAH patient lung ECs are attenuated by knocking down p16INK4A expression or treating with senolytic reagents. Knockdown of p16INK4A also suppresses accumulation of αSMA–positive cells to the supplemented ECs in the gel. Exosomes collected from hypoxia-treated mouse lung ECs stimulate SMC DNA synthesis and migration in vitro and in the gel implanted on the mouse lungs, while p16INK4A knockdown in ECs inhibits the effects. These results suggest that endothelial senescence controls αSMA–positive cell proliferation and migration in PH through TWIST1-PDGFB signaling.
2022-10-12 | GSE193272 | GEO