Tumor-associated macrophage-derived lactate remodels glioblastoma immune microenvironment through regulation of NHEJ repair by KU70 lactylation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1108672 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28926637.fastq.gz | Fastqsanger.gz | |||
| SRR28926638.fastq.gz | Fastqsanger.gz | |||
| SRR28926639.fastq.gz | Fastqsanger.gz | |||
| SRR28926640.fastq.gz | Fastqsanger.gz | |||
| SRR28926641.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:Glioblastoma (GBM) is a malignancy with a complex tumor microenvironment (TME) dominated by glioblastoma stem cells (GSCs) and infiltrated by tumor-associated macrophages (TAMs), and exhibits aberrant metabolic pathways. Lactate is a critical glycolytic metabolite that promotes tumor progression; however, the mechanisms of lactate transportation and lactylation in the tumor microenvironment (TME) of GBM remain elusive. Here, we found that the lactate metabolic signature was highly expressed in TAMs and tumor cells. Moreover, TAMs provide lactate to GSCs, promoting GSC proliferation and inducing lactylation of the non-homologous end joining (NHEJ) protein KU70 at the residue K317. TAM-derived lactate-mediated KU70 lactylation inhibits cGAS- type I interferon signaling, remodeling the immunosuppressive microenvironment through reduced cytotoxic CD8+ T cell infiltration, promoting the malignant progression of GBM. Combinatorial targeting of lactate transport and immune checkpoints demonstrated additive therapeutic benefit in immunocompetent orthotopic xenograft models. This study unveils TAM-derived lactate and lactylation as a critical regulator of NHEJ and create immunosuppressive microenvironment, linking the TME to DNA damage response in GBM and opening novel avenues for developing combinatorial therapy for GBM.
2024-06-01 | GSE266884 | GEO
Project description:Both metabolism reprogramming and DNA damage repair play critical roles in tumorigenesis and chemoresistance. However, the underlying mechanism linking the two pathways remains elusive. Here, we show that loss of lactate dehydrogenase A (LDHA) impairs non-homologous end joining (NHEJ) repair and reduces class switch recombination (CSR) in mice. In addition, we found that lactate, a metabolite of glycolysis, is involved in the regulation of NHEJ repair via XLF lactylation modification. Mechanically, upon DNA damage, GCN5 is phosphorylated by ATM, which promotes the interaction between GCN5 and XLF and stimulates the lactylation modification of XLF K288, which locates within the XLF Ku-binding motif (X-KBM). XLF lactylation enhances its interaction with Ku80, promotes XLF recruitment to DNA damage sites and elevates NHEJ efficiency. We solved the cryo-EM structure of Ku70/80 in complex with lactylated X-KBM (laX-KBM) and identified a new binding mode between Ku70/80 and XLF. laX-KBM interacts with Ku80 in a stretched and extended mode, resulting in conformational changes of the Ku80 vWA domain. Moreover, XLF lactylation deficiency impairs NHEJ and sensitizes cancer cells to chemotherapy. We designed a peptide specifically inhibiting XLF K288 lactylation, and combination of this peptide with 5-fluorouracil (5-FU) kill colorectal cancer cells more efficiently in PDX model with hyperactivation of XLF lactylation. Together, these results suggest that GCN5-XLF lactylation axis plays a key role in NHEJ stimulation and that targeting XLF lactylation might be a promising approach to improve chemotherapy efficiency in cancer.
2024-08-27 | PXD055315 |
Project description:Hexokinase catalyzes the first committed step in glucose metabolism by phosphorylating glucose to produce glucose-6-phosphate. Highly glycolytic proliferating cells such as cancer cells take advantage of HK2 expression to accelerate glucose metabolism even in the presence of oxygen. This acceleration not only provides sufficient glycolytic intermediates to support the anabolic demands of the cells but also inevitably accompanies increased formation of metabolic end products such as lactate. Currently, the effect of lactate caused by HK2-mediated metabolic alteration is largely unknown. A recent study found that lactate plays a role in an epigenetic alteration known as histone lactylation. Here, using RNA-seq and CUT&Tag chromatin profiling, we study the effect of HK2 and lactate on gene expression via histone lactylation (H3K18la).
2023-05-05 | GSE229153 | GEO
Project description:Hexokinase catalyzes the first committed step in glucose metabolism by phosphorylating glucose to produce glucose-6-phosphate. Highly glycolytic proliferating cells such as cancer cells take advantage of HK2 expression to accelerate glucose metabolism even in the presence of oxygen. This acceleration not only provides sufficient glycolytic intermediates to support the anabolic demands of the cells but also inevitably accompanies increased formation of metabolic end products such as lactate. Currently, the effect of lactate caused by HK2-mediated metabolic alteration is largely unknown. A recent study found that lactate plays a role in an epigenetic alteration known as histone lactylation. Here, using RNA-seq and CUT&Tag chromatin profiling, we study the effect of HK2 and lactate on gene expression via histone lactylation (H3K18la).
2023-05-05 | GSE229151 | GEO
Project description:In mammalian cells, classical non-homologous end joining (c-NHEJ) is critical for DNA double-strand break repair induced by ionizing radiation and during V(D)J recombination in developing B and T lymphocytes. Recently, PAXX was identified as a new c-NHEJ core component. We report here, that PAXX-deficient cells exhibit a cellular phenotype uncharacteristic of a deficiency in c-NHEJ core components. PAXX-deficient cells display normal sensitivity to radiomimetic drugs, are proficient in transient V(D)J recombination assays, and do not shift towards higher micro-homology usage in plasmid repair assays. Although PAXX-deficient cells lack c-NHEJ phenotypes, PAXX forms a ternary complex with Ku bound to DNA. Formation of this complex involves an interaction with Ku70 and requires a bare DNA extension for stability. Moreover, the relatively weak Ku-dependent stimulation of LIG4/XRCC4 activity by PAXX is unmasked by XLF ablation. Thus, PAXX plays an accessory role during c-NHEJ that is largely overlapping with XLF’s function.
2016-10-06 | PXD004659 | Pride
Project description:Cancer cells often rely on aerobic glycolysis for metabolism, and lactylation, a newly discovered post-translational modification, significantly impacts molecular processes. This study comprehensively analyzes lactylation's role in oral squamous cell carcinoma (OSCC), providing initial insights into its impact on progression. Oral squamous cell carcinoma cell lines, before and after lactate treatment, underwent CUT&TAG, ATAC, and transcriptomic sequencing. ChIP-qPCR and RT-qPCR validated results in OSCC tissues. Integrated analysis identified 217 genes with increased expression driven by lactylation in OSCC. Lactylation broadly impacted pathways in cancer, notably regulating PI3K/AKT and MAPK signaling. This pioneering study analyzes lactylation in OSCC, providing a global map of its regulation in oral squamous cell carcinoma from the perspective of chromatin-driven gene expression.
2024-08-20 | GSE249226 | GEO
Project description:Cancer cells often rely on aerobic glycolysis for metabolism, and lactylation, a newly discovered post-translational modification, significantly impacts molecular processes. This study comprehensively analyzes lactylation's role in oral squamous cell carcinoma (OSCC), providing initial insights into its impact on progression. Oral squamous cell carcinoma cell lines, before and after lactate treatment, underwent CUT&TAG, ATAC, and transcriptomic sequencing. ChIP-qPCR and RT-qPCR validated results in OSCC tissues. Integrated analysis identified 217 genes with increased expression driven by lactylation in OSCC. Lactylation broadly impacted pathways in cancer, notably regulating PI3K/AKT and MAPK signaling. This pioneering study analyzes lactylation in OSCC, providing a global map of its regulation in oral squamous cell carcinoma from the perspective of chromatin-driven gene expression.
2024-08-20 | GSE249224 | GEO
Project description:Cancer cells often rely on aerobic glycolysis for metabolism, and lactylation, a newly discovered post-translational modification, significantly impacts molecular processes. This study comprehensively analyzes lactylation's role in oral squamous cell carcinoma (OSCC), providing initial insights into its impact on progression. Oral squamous cell carcinoma cell lines, before and after lactate treatment, underwent CUT&TAG, ATAC, and transcriptomic sequencing. ChIP-qPCR and RT-qPCR validated results in OSCC tissues. Integrated analysis identified 217 genes with increased expression driven by lactylation in OSCC. Lactylation broadly impacted pathways in cancer, notably regulating PI3K/AKT and MAPK signaling. This pioneering study analyzes lactylation in OSCC, providing a global map of its regulation in oral squamous cell carcinoma from the perspective of chromatin-driven gene expression.
2024-08-20 | GSE249223 | GEO
Project description:Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades anti-tumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming towards glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of microglial phagocytosis via transcriptional upregulation of CD47, a “don’t eat me” signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) P300 to induce increased P300 substrate specificity toward lactyl-coA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates a metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immune-oncology therapies.
2023-10-26 | GSE245854 | GEO
Project description:Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades anti-tumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming towards glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of microglial phagocytosis via transcriptional upregulation of CD47, a “don’t eat me” signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) P300 to induce increased P300 substrate specificity toward lactyl-coA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates a metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immune-oncology therapies.
2023-10-26 | GSE245853 | GEO