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Hypoxic Memory Mediates Prolonged Tumor Intrinsic Type I Interferon Suppression to Promote Breast Cancer Progression [scRNA-seq]

ABSTRACT: Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIFs). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell (CTC) lines and common breast cancer cell lines, hypoxia downregulated tumor intrinsic type I interferon (IFN) signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a “hypoxic memory” phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor (HDACi) entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for CTCs during the metastatic cascade.

ORGANISM(S): Mus musculus

PROVIDER: GSE270295 | GEO | 2024/06/28

REPOSITORIES: GEO

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Hypoxic Memory Mediates Prolonged Tumor Intrinsic Type I Interferon Suppression to Promote Breast Cancer Progression [RNA-Seq]

Project description:Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIFs). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell (CTC) lines and common breast cancer cell lines, hypoxia downregulated tumor intrinsic type I interferon (IFN) signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a “hypoxic memory” phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor (HDACi) entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for CTCs during the metastatic cascade.

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Hypoxia modulates EWS-FLI1 transcriptional signature and enhances malignant properties of Ewing’s tumor cells in vitro

Project description:Hypoxia is an important condition in the tumor cell microenvironment and approximately 1-1.5% of the genome is transcriptionally responsive to hypoxia with hypoxia-inducible factor-1 (HIF-1) as a major mediator of transcriptional activation. Tumor hypoxia is associated with a more aggressive phenotype of many cancers in adults, but data on pediatric tumors are scarce. By immunohistochemical analysis, HIF-1α expression was readily detectable in 18/28 primary Ewing´s sarcoma family tumors (ESFT), a group of highly malignant bone-associated tumors in children and young adults, which encouraged us to study the effect of hypoxia on ESFT cell lines in vitro. Many tumors are profoundly hypoxic and multiple studies have demonstrated that hypoxic tumors have a poorer prognosis than non-hypoxic tumors. The cellular adaptations of cancer cells to hypoxia have been shown to profoundly influence transcriptional regulation. Intriguingly, we found that EWS-FLI1 protein expression, which characterizes ESFT, is up-regulated by hypoxia in a HIF-1α-dependent manner. Hypoxia modulated the EWS-FLI1 transcriptional signature relative to normoxic conditions. Both synergistic as well as antagonistic transcriptional effects of EWS-FLI1 and of hypoxia were observed. Consistent with alterations in the expression of metastasis related genes, hypoxia stimulated the invasiveness and soft-agar colony formation of ESFT cells in vitro. Our data represents the first transcriptome analysis of hypoxic ESFT cells and identifies hypoxia as an important microenvironmental factor modulating EWS-FLI1 expression and target gene activity with far-reaching consequences for the malignant properties of ESFT. Experiment Overall Design: We analysed the consequences of hypoxia on gene expression in two ESFT cell lines (SK-N-MC, TC252) grown as multicellular spheroids and as adherent monolayers.

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Project description:Genome wide DNA methylation profiling of normoxic and hypoxic non-small-cell lung cancer samples for 5mC and 5hmC. The Illumina Infinium 450k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation and hydroxymethylation profiles across 485,512 CpGs from DNA extracted from fresh-frozen tumor samples. Samples included 12 hypoxic and 12 normoxic tumor samples, with hypoxia determined according to the hypoxia metagene score (Buffa et al, Br J Cancer 2010). To profile hydroxymethylation, 5hmC was glycosylated and 5mC was oxidised as described by Yu and colleagues (Nat Protoc 2012), and hydroxymethylation and methylation were differentially profiled according to the Nazor and colleagues (Genomics 2014). Hypermethylation of tumor suppressor gene (TSG) promoters confers growth advantages to cancer cells, but how these changes arise is poorly understood. Here, we report that tumor hypoxia reduces the activity of oxygen-dependent TET enzymes, which catalyze DNA de-methylation through 5-methylcytosine oxidation. This occurs independently of hypoxia-associated alterations in TET gene expression, basal metabolism, HIF activity or nuclear reactive oxygen species, but directly depends on oxygen shortage. Hypoxia-induced loss of TET activity increases hypermethylation at gene promoters in vitro, while also in patients, gene promoters are markedly more methylated in hypoxic than normoxic tumors. Affected genes are frequently involved in DNA repair, cell cycle regulation, angiogenesis and metastasis, indicating cellular selection of hypermethylation events. Overall, up to 50% of the tumor-associated hypermethylation is ascribable to hypoxia across various cancer types. Accordingly, spontaneous murine breast tumors become hypermethylated when rendered hypoxic through vessel pruning, whereas vessel normalisation rescues this effect. Tumor hypoxia thus acts as a novel regulator underlying DNA methylation.

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Project description:Analysis of the binding sites of Hif-1Î± in both wild-type and von Hippel Lindau mutant zebrafish lines at 4dpf by ChIP linked next generation sequencing. The von Hippel Lindau mutant displays a systemic hypoxic response under normoxic conditions. Results show the extent of Hif-1Î± binding to the genome, and provide a basis for analysis of the transcriptional response to genetically induced hypoxia in zebrafish. Analysis of the DNA binding sites of Hif-1Î± in both wild-type and von Hippel Lindau mutant zebrafish lines at 4dpf. The von Hippel Lindau mutant displays a systemic hypoxic response under normoxic conditions. Results show the extent of Hif-1Î± binding to the genome, and provide a basis for analysis of the dependency of the transcriptional response on Hif-1Î± in conditions of genetically induced hypoxia in zebrafish.

2016-03-22 | E-GEOD-70727 | biostudies-arrayexpress

Tumor hypoxia causes DNA hypermethylation by reducing TET activity (TAB-Seq)

Project description:Hypermethylation of tumor suppressor gene (TSG) promoters confers growth advantages to cancer cells, but how these changes arise is poorly understood. Here, we report that tumor hypoxia reduces the activity of oxygen-dependent TET enzymes, which catalyze DNA de-methylation through 5-methylcytosine oxidation. This occurs independently of hypoxia-associated alterations in TET gene expression, basal metabolism, HIF activity or nuclear reactive oxygen species, but directly depends on oxygen shortage. Hypoxia-induced loss of TET activity increases hypermethylation at gene promoters in vitro, while also in patients, gene promoters are markedly more methylated in hypoxic than normoxic tumors. Affected genes are frequently involved in DNA repair, cell cycle regulation, angiogenesis and metastasis, indicating cellular selection of hypermethylation events. Overall, up to 50% of the tumor-associated hypermethylation is ascribable to hypoxia across various cancer types. Accordingly, spontaneous murine breast tumors become hypermethylated when rendered hypoxic through vessel pruning, whereas vessel normalisation rescues this effect. Tumor hypoxia thus acts as a novel regulator underlying DNA methylation.

2016-09-01 | GSE71402 | GEO

Tumor hypoxia causes DNA hypermethylation by reducing TET activity (RNA-Seq)

2016-09-01 | GSE71401 | GEO

Tumor hypoxia causes DNA hypermethylation by reducing TET activity (DIP-Seq)

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Tumor hypoxia causes DNA hypermethylation by reducing TET activity (Bisulfite-Seq)

2016-09-01 | GSE71399 | GEO

Hypoxia modulates EWS-FLI1 transcriptional signature and enhances malignant properties of Ewing’s tumor cells in vitro

Project description:Hypoxia is an important condition in the tumor cell microenvironment and approximately 1-1.5% of the genome is transcriptionally responsive to hypoxia with hypoxia-inducible factor-1 (HIF-1) as a major mediator of transcriptional activation. Tumor hypoxia is associated with a more aggressive phenotype of many cancers in adults, but data on pediatric tumors are scarce. By immunohistochemical analysis, HIF-1α expression was readily detectable in 18/28 primary Ewing´s sarcoma family tumors (ESFT), a group of highly malignant bone-associated tumors in children and young adults, which encouraged us to study the effect of hypoxia on ESFT cell lines in vitro. Many tumors are profoundly hypoxic and multiple studies have demonstrated that hypoxic tumors have a poorer prognosis than non-hypoxic tumors. The cellular adaptations of cancer cells to hypoxia have been shown to profoundly influence transcriptional regulation. Intriguingly, we found that EWS-FLI1 protein expression, which characterizes ESFT, is up-regulated by hypoxia in a HIF-1α-dependent manner. Hypoxia modulated the EWS-FLI1 transcriptional signature relative to normoxic conditions. Both synergistic as well as antagonistic transcriptional effects of EWS-FLI1 and of hypoxia were observed. Consistent with alterations in the expression of metastasis related genes, hypoxia stimulated the invasiveness and soft-agar colony formation of ESFT cells in vitro. Our data represents the first transcriptome analysis of hypoxic ESFT cells and identifies hypoxia as an important microenvironmental factor modulating EWS-FLI1 expression and target gene activity with far-reaching consequences for the malignant properties of ESFT. Keywords: Consequences on gene expression of hypoxic condition created by exposure of cells to 1% oxygen in a hypoxia chamber.

2010-05-26 | GSE19197 | GEO

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Project description:Comprehensive analysis of coding and non -coding transcriptome using ribo-depleted total RNA-seq and poly A selected RNA-seq of MCF-7 cells grown in hypoxia and normoxia. Breast cancer cell line (MCF-7) is cultured in normoxic condition (21% O2) and hypoxic condition (1%O2) for 24 hours. Expression of HIF-1alpha and/or HIF-2alpha subunits was suppressed using siRNAs in hypoxic MCF-7 cells. Total RNA was isolated from both hypoxia and normoxia conditions were subjected for ribosomal depleted stand specific RNA-seq and poly A selected RNA-seq

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