Ontology highlight
ABSTRACT:
PROVIDER: PRJNA602543 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10947533_1.fastq.gz | Fastqsanger.gz | |||
| SRR10947533_2.fastq.gz | Fastqsanger.gz | |||
| SRR10947534_1.fastq.gz | Fastqsanger.gz | |||
| SRR10947534_2.fastq.gz | Fastqsanger.gz | |||
| SRR10947535_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 14 |
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Project description:The lactate receptor GPR81 contributes to cancer development, yet the mechanisms remain unclear. Here, we show that GPR81 is upregulated in human cancers and further upregulated by extracellular lactate and three-dimensional growth of breast cancer spheroids. GPR81 knockdown (KD) increased spheroid necrosis and reduced invasion and in vivo tumor growth. GPR81 KD altered GO terms relating to extracellular matrix (ECM) and cell adhesion, including upregulation of Protocadherin-7 (PCDH7), which exhibited a striking, clustered expression in spheroids. Single cell analysis revealed that PCDH7 was inversely related with Ki-67 and co-clustered with other GPR81 KD-upregulated genes including Ephrin-type-A receptor-7 (EPHA7). The matricellular protein SPARC and the Notch ligand Delta-like-4 (DLL4), were downregulated upon GPR81 KD, and their KD elicited spheroid necrosis (DLL4) and inhibited invasion. We conclude that GPR81 supports breast cancer aggressiveness at least in part via SPARC and DLL4. Our findings substantiate GPR81 as a promising target in breast cancer treatment.
2022-05-23 | GSE203441 | GEO
Project description:Interactions between acute myeloid leukemia (AML) and the bone marrow microenvironment (BMME) are critical to leukemia progression and chemoresistance. In the solid tumor microenvironment, altered metabolite levels contribute to cancer progression. We performed a metabolomic analysis of AML patient bone marrow serum, revealing increased metabolites compared to age- and sex-matched controls. The most highly elevated metabolite in the AML BMME was lactate. Lactate signaling in solid tumors induces immunosuppressive tumor-associated macrophages and correlates with poor prognosis. This has not yet been studied in the leukemic BMME. Herein, we describe the role of lactate in the polarization of leukemia-associated macrophages (LAMs). Using a murine AML model of blast crisis chronic myelogenous leukemia (bcCML), we characterize the suppressive phenotype of LAMs by surface markers, transcriptomics, and cytokine profiling. Then, mice genetically lacking GPR81, the extracellular lactate receptor, were used to demonstrate GPR81 signaling as a mechanism of both the polarization of LAMs and the direct support of leukemia cells. Furthermore, elevated lactate diminished the function of hematopoietic progenitors and reduced stromal support for normal hematopoiesis. We report microenvironmental lactate as a mechanism of AML-induced immunosuppression and leukemic progression, thus identifying GPR81 signaling as an exciting and novel therapeutic target for treating this devastating disease.
2026-03-11 | GSE313457 | GEO
Project description:Metabolic reprogramming an immune evasion are established hallmarks of the tumor microenvironment (TME). Growing evidence supports tumor metabolic dysregulation as an important mediator of tumor immune evasion. High TME levels of lactate potently suppress antitumor immunity. Pyruvate carboxylase (PC), responsible for the anaplerotic conversion of pyruvate to oxaloacetate, is essential for lung metastasis in breast cancer. Conversely, PC may be dispensable in some cells in the TME, with loss of PC associated with immunosuppression. Here we test whether PC suppression alters tumor metabolism and immunosuppression. Using multiple animal models of breast cancer, we identify a dimorphic role for PC expression in mammary cancer cells. PC supports metastatic colonization of the lungs; however, depletion of PC promotes primary tumor growth and suppresses histological and transcriptomic markers of antitumor immunity. We demonstrate that PC is potently suppressed by hypoxia, and that PC suppression is common in solid tumors, particularly those with higher levels of hypoxia. Using metabolomics, high resolution respirometry, and extracellular flux analysis, we show that PC-depleted cells produce more lactate and undergo less oxidative phosphorylation than scramble controls. Finally, we identify lactate metabolism as a targetable dependency of PC-depleted cells, which is sufficient to restore T cell populations to the TME of PC-depleted tumors. Taken together these data demonstrate that elevated lactate following PC suppression by hypoxia may be a key mechanism through which primary tumors limit antitumor immunity. Thus, these data highlight PC directed tumor metabolism is a nexus of tumor progression and antitumor immunity.
2023-12-29 | GSE199828 | GEO
Project description:Metabolic reprogramming an immune evasion are established hallmarks of the tumor microenvironment (TME). Growing evidence supports tumor metabolic dysregulation as an important mediator of tumor immune evasion. High TME levels of lactate potently suppress antitumor immunity. Pyruvate carboxylase (PC), responsible for the anaplerotic conversion of pyruvate to oxaloacetate, is essential for lung metastasis in breast cancer. Conversely, PC may be dispensable in some cells in the TME, with loss of PC associated with immunosuppression. Here we test whether PC suppression alters tumor metabolism and immunosuppression. Using multiple animal models of breast cancer, we identify a dimorphic role for PC expression in mammary cancer cells. PC supports metastatic colonization of the lungs; however, depletion of PC promotes primary tumor growth and suppresses histological and transcriptomic markers of antitumor immunity. We demonstrate that PC is potently suppressed by hypoxia, and that PC suppression is common in solid tumors, particularly those with higher levels of hypoxia. Using metabolomics, high resolution respirometry, and extracellular flux analysis, we show that PC-depleted cells produce more lactate and undergo less oxidative phosphorylation than scramble controls. Finally, we identify lactate metabolism as a targetable dependency of PC-depleted cells, which is sufficient to restore T cell populations to the TME of PC-depleted tumors. Taken together these data demonstrate that elevated lactate following PC suppression by hypoxia may be a key mechanism through which primary tumors limit antitumor immunity. Thus, these data highlight PC directed tumor metabolism is a nexus of tumor progression and antitumor immunity.
2023-12-29 | GSE199830 | GEO
Project description:Metabolic reprogramming an immune evasion are established hallmarks of the tumor microenvironment (TME). Growing evidence supports tumor metabolic dysregulation as an important mediator of tumor immune evasion. High TME levels of lactate potently suppress antitumor immunity. Pyruvate carboxylase (PC), responsible for the anaplerotic conversion of pyruvate to oxaloacetate, is essential for lung metastasis in breast cancer. Conversely, PC may be dispensable in some cells in the TME, with loss of PC associated with immunosuppression. Here we test whether PC suppression alters tumor metabolism and immunosuppression. Using multiple animal models of breast cancer, we identify a dimorphic role for PC expression in mammary cancer cells. PC supports metastatic colonization of the lungs; however, depletion of PC promotes primary tumor growth and suppresses histological and transcriptomic markers of antitumor immunity. We demonstrate that PC is potently suppressed by hypoxia, and that PC suppression is common in solid tumors, particularly those with higher levels of hypoxia. Using metabolomics, high resolution respirometry, and extracellular flux analysis, we show that PC-depleted cells produce more lactate and undergo less oxidative phosphorylation than scramble controls. Finally, we identify lactate metabolism as a targetable dependency of PC-depleted cells, which is sufficient to restore T cell populations to the TME of PC-depleted tumors. Taken together these data demonstrate that elevated lactate following PC suppression by hypoxia may be a key mechanism through which primary tumors limit antitumor immunity. Thus, these data highlight PC directed tumor metabolism is a nexus of tumor progression and antitumor immunity.
2023-12-29 | GSE199829 | GEO
Project description:Skeletal muscle aging is associated with increased lipid accumulation, or myosteatosis, leading to lipotoxicity and loss of muscle function. Here, we report that loss of the novel lactate receptor GPR81 in aged muscle is associated with impaired lipid oxidation and enhanced lipid accumulation. Knockdown of GPR81 in young healthy myoblasts led to an increase in senescence hallmarks such as DNA damage, accumulation of reactive oxygen species (ROS), mitochondrial dysfunction and impaired autophagy. Conversely, treatment of senescent myoblasts with GPR81 agonists enhanced lipid oxidation in senescent myoblasts leading to a decrease in lipid accumulation, ultimately resulting in decreased DNA damage, ROS accumulation and enhanced ability to form myotubes. In agreement with our in vitro findings, we observed significant improvement in muscle regeneration and overall health of aged or progeric mice that were treated with GPR81 agonists. Our findings suggest that GPR81 plays a key role in skeletal muscle lipid metabolism, and agonists of GPR81 might play a promising role in reversing age-associated lipid accumulation and loss of muscle function.
2026-06-01 | GSE325224 | GEO
Project description:Overcoming endocrine-resistance is the major challenge in treating Estrogen receptor (ER)-positive breast cancer. Breast Cancer Stem Cells (BCSCs) are blamed to be the driving force behind poor clinical outcomes and therapeutic resistance. Tumor microenvironment (TME) exerts a selective pressure on the tumor, supporting BCSCs behavior. The most prevalent cellular component of breast TME is represented by adipocytes, which secrete reduced levels of adiponectin in obesity, promoting ERα-positive breast cancer growth and progression. We examined the impact of low adiponectin levels on the enrichment of BCSC subpopulations and the molecular mechanisms by which this may contribute to hormone-resistance in breast cancer.
2025-05-07 | PXD059964 | Pride
Project description:Exercise links with improved cancer outcomes following a diagnosis of primary breast cancer but experimental evidence from preclinical studies and molecular mechanistic insights are limited. Here, we show that exercise inhibits breast cancer growth and metastases across multiple syngeneic mouse models compared to sham control. Utilizing the Met1-iRFP model to interrogate tumor microenvironmental (TME) and tumor-specific effects, exercise decreased intratumoral immune cell content, particularly tumor-associated macrophages, and prompted an activated anticancer innate immune response. Cancer cell-intrinsic effects were characterized by broad transcriptomic reprogramming including downregulation of metabolic pathways and upregulation of pathways regulating proliferation and apoptosis. Metabolomic analyses unveiled broad shifts in tumor metabolism including decreased NAD+ and lactate, as well as availability of biosynthetic precursors. Finally, in silico analyses identified TME ligands such as Hmgb2 as drivers of downstream gene expression changes in cancer cells. Collectively, our findings show that exercise suppresses breast cancer progression and does so via broad reprogramming of TME-cancer components and their interaction.
2026-05-01 | GSE304653 | GEO
Project description:Glioblastoma (GBM) is a malignancy with a complex tumour microenvironment (TME) dominated by GBM stem cells (GSCs) and infiltrated by tumour-associated macrophages (TAMs) and exhibits aberrant metabolic pathways. Lactate is a critical glycolytic metabolite that promotes tumour progression; however, the mechanisms of lactate transport and lactylation in the TME of GBM remain elusive. Here we show that lactate is transported from TAMs to GSCs via MCT4–MCT1. TAMs provide lactate to GSCs, promoting GSC proliferation and inducing lactylation of the non-homologous end joining protein KU70 at lysine 317 (K317), which inhibits cGAS–STING signalling and remodels the immunosuppressive TME. Inhibition of lactate transport or targeting the lactylation of KU70, in combination with the immune checkpoint blockade, demonstrates additive therapeutic benefits in immunocompetent xenograft models. This study unveils TAM-derived lactate and lactylation as critical regulators in GSCs to enforce an immunosuppressive microenvironment, opening avenues for developing combinatorial therapy for GBM.
2024-06-01 | GSE266884 | GEO