Single cell RNA-sequence reveals the transcriptional dynamics of tumor immune micrenvironment by LDHA inhibition in cancer cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE254189 | GEO | 2024/10/09
REPOSITORIES: GEO
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Project description:Metabolic reprogramming, due in part to the overexpression of metabolic enzymes, is a key hallmark of cancer cells. Lactate dehydrogenase (LDHA), a metabolic enzyme that catalyzes the interconversion of lactate and pyruvate, is overexpressed in a wide variety of cancer types, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, the genetic or pharmacological inhibition of LDHA suppresses cancer growth, demonstrating a cancer-promoting role for this enzyme. Therefore, several pharmacological LDHA inhibitors are being developed and tested as potential anti-cancer therapeutic agents. Because cancer cells are known to rapidly adapt and become resistant to anti-cancer therapies, in this study, we modeled the adaptation of cancer cells to LDHA inhibition. Using PDAC as a model system, we studied the molecular aspects of cells resistant to the competitive LDHA inhibitor sodium oxamate. We performed unbiased RNA-sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), and metabolomics analyses of parental and oxamate-resistant PDAC cells treated with and without oxamate to identify the transcriptional, chromatin, and metabolic landscapes of these cells. We found that oxamate-resistant PDAC cells were significantly different from parental cells at the levels of mRNA expression, chromatin accessibility, and metabolites. Additionally, an integrative analysis combining the RNA-seq and ATAC-seq datasets identified a subset of differentially expressed mRNAs that directly correlated with changes in chromatin accessibility. Finally, functional analysis of differentially expressed metabolic genes in parental and oxamate-resistant PDAC cells treated with and without oxamate, together with an integrative analysis of RNA-seq and metabolomics data, revealed changes in metabolic enzymes that might explain the changes in metabolite levels observed in these cells. Collectively, these studies identify the transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor resistance in PDAC cells. Future functional studies related to these changes remain necessary to reveal the direct roles played by these changes in the development of LDHA inhibitor resistance and uncover approaches for more effective use of LDHA inhibitors in cancer therapy.
2022-08-02 | GSE164976 | GEO
Project description:Metabolic reprogramming, due in part to the overexpression of metabolic enzymes, is a key hallmark of cancer cells. Lactate dehydrogenase (LDHA), a metabolic enzyme that catalyzes the interconversion of lactate and pyruvate, is overexpressed in a wide variety of cancer types, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, the genetic or pharmacological inhibition of LDHA suppresses cancer growth, demonstrating a cancer-promoting role for this enzyme. Therefore, several pharmacological LDHA inhibitors are being developed and tested as potential anti-cancer therapeutic agents. Because cancer cells are known to rapidly adapt and become resistant to anti-cancer therapies, in this study, we modeled the adaptation of cancer cells to LDHA inhibition. Using PDAC as a model system, we studied the molecular aspects of cells resistant to the competitive LDHA inhibitor sodium oxamate. We performed unbiased RNA-sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), and metabolomics analyses of parental and oxamate-resistant PDAC cells treated with and without oxamate to identify the transcriptional, chromatin, and metabolic landscapes of these cells. We found that oxamate-resistant PDAC cells were significantly different from parental cells at the levels of mRNA expression, chromatin accessibility, and metabolites. Additionally, an integrative analysis combining the RNA-seq and ATAC-seq datasets identified a subset of differentially expressed mRNAs that directly correlated with changes in chromatin accessibility. Finally, functional analysis of differentially expressed metabolic genes in parental and oxamate-resistant PDAC cells treated with and without oxamate, together with an integrative analysis of RNA-seq and metabolomics data, revealed changes in metabolic enzymes that might explain the changes in metabolite levels observed in these cells. Collectively, these studies identify the transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor resistance in PDAC cells. Future functional studies related to these changes remain necessary to reveal the direct roles played by these changes in the development of LDHA inhibitor resistance and uncover approaches for more effective use of LDHA inhibitors in cancer therapy.
2022-08-02 | GSE164974 | GEO
Project description:In this study, we investigated the impact of autophagy inhibition in cancer cell on the tumor immune microenvironment (TIME) of orthotopic syngeneic pancreatic ductal adenocarcinoma (PDAC) tumors. Dendritic cells (DCs) in the cancer cell autophagy inhibited tumors showed significantly higher expression of genes related to DC functions such as antigen-presentation, migration, IFN response, compared to control tumors. Our results indicate that autophagy inhibition in cancer cells induce the enhancement of adoptive tumor immunity via DC activation in PDAC.
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Project description:Following infection or vaccination, activated B cells at extrafollicular sites or within germinal centers (GCs) undergo vigorous clonal proliferation. Proliferating lymphocytes have been shown to undertake lactate dehydrogenase A (LDHA)-dependent aerobic glycolysis; however, the specific role of this metabolic pathway in a B cell transitioning from a naïve to a highly proliferative, activated state remains poorly defined. Here, we deleted LDHA in a stage- and cell-specific manner. We find that ablation of LDHA in a naïve B cell did not profoundly affect its ability to undergo a T cell-independent extrafollicular B cell response. On the other hand, LDHA-deleted naïve B cells had a severe defect in the capacities to form GCs and mount GC-dependent antibody responses. In addition, loss of LDHA in T cells severely compromised B cell-dependent immune responses. Strikingly, when LDHA was deleted in activated, as opposed to naïve, B cells, there were only minimal effects on the GC reaction and in the generation of high-affinity antibodies. These findings strongly suggest that naïve and activated B cells have distinct metabolic requirements that are further regulated by niche and cellular interactions.
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Project description:Protein lactylation is a process that is fueled by lactate, generated by the enzyme lactate dehydrogenase (Ldh) from pyruvate. Despite prior research, the precise role of protein lactylation in controlling the identity of mouse embryonic stem cells (ESCs) is still not fully understood. We observed that inhibiting or eliminating Ldha causes a reduction in global protein lactylation in ESCs, and RNA-seq analysis suggests that Ldha inhibition induces a 2-cell-like cell (2CLC) signature in ESCs. To probe the underlying mechanisms, we performed quantitative lactylation proteomics analysis, we discovered that Hdac1, a gene with significant regulatory roles during the 2-cell stage (2C), undergoes lactylation modification. Additionally, we observed that treatment with an Ldh (lactate dehydrogenase) inhibitor can decrease the lactylation levels of Hdac1. Mechanistically, we discovered that Ldha positively regulates the lactylation of Hdac1, promoting its direct binding to zygotic genome activation (ZGA) gene promoters and has stronger deacetylase activity. This leads to the removal of acetyl groups from H3K27 on these loci, effectively suppressing the expression of 2C genes. Our study presents novel evidence supporting protein lactylation's potential as a means of inhibiting the generation of 2CLCs and modulating acetylation activity.
2024-11-07 | GSE247959 | GEO
Project description:Protein lactylation is a process that is fueled by lactate, generated by the enzyme lactate dehydrogenase (Ldh) from pyruvate. Despite prior research, the precise role of protein lactylation in controlling the identity of mouse embryonic stem cells (ESCs) is still not fully understood. We observed that inhibiting or eliminating Ldha causes a reduction in global protein lactylation in ESCs, and RNA-seq analysis suggests that Ldha inhibition induces a 2-cell-like cell (2CLC) signature in ESCs. To probe the underlying mechanisms, we performed quantitative lactylation proteomics analysis, we discovered that Hdac1, a gene with significant regulatory roles during the 2-cell stage (2C), undergoes lactylation modification. Additionally, we observed that treatment with an Ldh (lactate dehydrogenase) inhibitor can decrease the lactylation levels of Hdac1. Mechanistically, we discovered that Ldha positively regulates the lactylation of Hdac1, promoting its direct binding to zygotic genome activation (ZGA) gene promoters and has stronger deacetylase activity. This leads to the removal of acetyl groups from H3K27 on these loci, effectively suppressing the expression of 2C genes. Our study presents novel evidence supporting protein lactylation's potential as a means of inhibiting the generation of 2CLCs and modulating acetylation activity.
2024-11-07 | GSE247958 | GEO
Project description:LDHA is key enzyme for tumor glycolysis metabolism and knocking down LDHA would change a lot of gene expression We used microarrays to detail the global gene expression in 4T1 cells with LDHA knocked down by shRNA
2017-09-16 | GSE103925 | GEO
Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.
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Project description:Histone acetylation involves the transfer of a two-carbon unit to nucleus as embedded in low-concentration metabolites. We find that lactate, a high-concentration metabolic by-product, can be a major carbon source for histone acetylation, through oxidation-dependent metabolism. Both in cells and in purified nucleus, 13C3-lactate carbons are incorporated into histone H4 (maximum incorporation: ~60%). In purified nucleus, this process depends on nucleus-localized lactate dehydrogenase (LDHA), the knockout of which abrogates the incorporation. Heterologous expression of nucleus-localized LDHA rescues the KO effect. Lactate itself increases histone acetylation, whereas inhibition of LDHA reduces the acetylation. In vitro and in vivo settings exhibit different lactate incorporation patterns, suggesting an influence of the microenvironment. Higher nuclear LDHA localization is observed in pancreatic cancer than in normal tissues, showing the disease relevance. Overall, lactate and nuclear LDHA can be major structural and regulatory players in the metabolism-epigenetics axis controlled by cell’s own or environmental status.
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