Pseudohypoxia Due to PHD2 Deficiency Induces Endothelial Resistance to Apoptosis and Inflammation Independent of HIF2 alpha via AKT Activation and AIP1 Loss
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PROVIDER: PRJNA1051629 | ENA |
REPOSITORIES: ENA
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Project description:PHD2 silencing activated AKT and ERK, inhibited JNK, and decreased AIP1, inhibiting apoptosis and proliferation and activating STAT. Like PHD2, AIP1 silencing affected the same kinase pathways and produced a similar dysfunctional endothelial cell phenotype, which was at least partially reversible with AKT inhibition. Transcriptomic profiling of human lung microvascular endothelial cells revealed that silencing PHD2 or AIP1 both induced an IFN/STAT-biased inflammatory signature with repression of E2F and MYC target genes. These in vitro results mirrored findings in lung vascular endothelial cells and tissues from PAH patients as well as rodent models of PAH. PHD2 deficiency in human lung vascular endothelial cells induced an apoptosis-resistant, inflammatory, and hypo-proliferative phenotype. AKT activation and AIP1 loss, but not HIF signaling, drove these phenotypic aberrations.
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Project description:Radiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to prevent or mitigate GI radiotoxicity. The EGLN protein family are oxygen sensors that regulate cell survival and metabolism through the degradation of hypoxia-inducible factors (HIFs). Our group has previously shown that stabilization of HIF2 through genetic deletion or pharmacologic inhibition of the EGLNs mitigates and protects against GI radiotoxicity in mice by improving intestinal crypt stem cell survival. Here we aimed to elucidate the molecular mechanisms by which HIF2 confers GI radioprotection. We developed duodenal organoids from mice, transiently overexpressed non-degradable HIF2, and performed bulk RNA sequencing. Interestingly, HIF2 upregulated known radiation modulators and genes involved in GI homeostasis, including Wnt5a. Non-canonical Wnt5a signaling has been shown by other groups to improve intestinal crypt regeneration in response to injury. Here we show that HIF2 drives Wnt5a expression in multiple duodenal organoid models. Luciferase reporter assays performed in human cells showed that HIF2 directly activates the WNT5A promoter via a hypoxia response element. We then evaluated crypt regeneration using spheroid formation assays. Duodenal organoids that were pre-treated with recombinant Wnt5a had a higher cryptogenic capacity after irradiation, compared to vehicle-treated organoids. Conversely, we found that Wnt5a knockout decreased the cryptogenic potential of intestinal stem cells following irradiation. Treatment with recombinant Wnt5a prior to irradiation rescued the cryptogenic capacity of Wnt5a knockout organoids, indicating that Wnt5a is necessary and sufficient for duodenal radioprotection. Taken together, our results.txt suggest that HIF2 radioprotects the GI tract by inducing Wnt5a expression.
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Project description:To identify novel regulator of EGLN1/PHD2, we performed label-free quantitative interactome analysis. Stable Hela cell lines expressing Flag-tagged PHD2 and control vector were generated. Immunoprecipitation and mass spectrometry analysis were performed to identify novel interactors of PHD2 followed by validation and functional analysis.
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Project description:To study the cell composition and gene expression profile in the mesendoderm differentiation of WT and PHD2 knockout, we performed scRNA-seq on the cells collected from the differentiation of WT and PHD2 knockout AB2.2 mESCs at differentiation day 4. PHD2 knockoutout mESCs were constructed by CRISPR/Cas9. The differentiation was performed using a non-lineage tendency differentiation protocol.
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Project description:We used a dual recombinase mouse model to delete Hif2a in α-smooth muscle actin (αSMA)-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF-Hif2a expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, a HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade. Results. CAF-specific deletion of HIF2, but not HIF1, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = 0.0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models. Conclusions. Together, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.
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Project description:Triple-negative breast cancer (TNBC) is difficult to treat due to the lack of biological targets and poor sensitivity to conventional therapies. Chemotherapy is the main treatment in the clinic, but there is still no effective screening strategy for chemotherapy drugs. Several studies have attempted to find the pathogenesis through sequencing, but the integration of transcriptome maps of various tumors for drug discovery has been slow. Drug repurposing has attracted increasing attention in recent years. We first found there were common features between leukemia and TNBC. Therefore, we chose a classic leukemia drug thioguanine (6-TG) as a candidate drug. We utilized RNA-seq and DNA methylation arrays to evaluate its role in MDA-MB-231 cells. Our results demonstrated that 6-TG inhibited cell proliferation by suppressing PI3K-AKT pathway via downregulating the DNA methylation level of PTEN. Moreover, apoptosis was induced via the activation of PI3K-AKT downstream molecular TSC1 and the downregulation of methylation levels of DAXX, TNF, FADD and CASP8 etc., these genes involved in apoptosis pathways. 6-TG presents anti-tumor effects in vitro and vivo by regulating the DNA methylation levels of PI3K-AKT pathway and apoptosis pathway. Meanwhile, we proved transcriptome-based drug screening has potential implications for breast cancer therapy and drug selection.
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Project description:Background & Aims. Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma, which contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown. Methods. We used a dual recombinase mouse model to delete Hif1a or Hif2a in α-smooth muscle actin (αSMA)-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF-Hif2a expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, a HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade. Results. CAF-specific deletion of HIF2, but not HIF1, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = 0.0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models. Conclusions. Together, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.
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