The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade
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ABSTRACT:
PROVIDER: PRJNA1098755 | ENA |
REPOSITORIES: ENA
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Project description:Cultured cancer cells frequently rely on the consumption of glutamine and its subsequent hydrolysis to glutamate by the mitochondrial enzyme glutaminase (GLS). However, this metabolic addiction can be lost in the tumor microenvironment (TME), rendering GLS inhibitors ineffective in the clinic. Here, we show that seemingly glutamine-addicted breast cancer cells ultimately adapt to chronic glutamine starvation, or targeted GLS inhibition, via the AMPK-mediated upregulation of the serine synthesis pathway (SSP). In this context, the key product of the SSP is not serine itself, but a-ketoglutarate (a-KG). Mechanistically, we find that the phylogenetically distinct transaminase phosphoserine aminotransferase 1 (PSAT1) has a unique capacity for sustained a-KG production when glutamate is severely depleted. Breast cancer cells with intrinsic or acquired resistance to glutamine starvation or GLS inhibition are highly dependent on SSP-supplied a-KG. Accordingly, pharmacological disruption of the SSP prevents adaptation to glutamine blockade, yielding a potent drug synergism that abolishes breast tumor growth in vivo. These findings highlight how metabolic redundancy can be context dependent, with the catalytic properties of different metabolic enzymes that act on the same substrate determining which pathways can support tumor growth in a particular nutrient environment. This in turn has practical consequences for therapies targeting cancer metabolism.
2024-07-05 | GSE263696 | GEO
Project description:Angiogenesis, the formation of new blood vessels from pre-existing ones, is a complex and demanding biological process that plays an important role in physiological as well as pathological settings such as cancer and ischemia. Given its critical role, the regulation of endothelial growth factor receptor (e.g. VEGFR2, FGFR1) represents important mechanisms for the control of angiogenesis. Recent evidences support cell metabolism as a critical regulator of angiogenesis. However, it is unknown how glutamine metabolism regulates growth factor receptor expression. Here, by using genetic and pharmacological approaches, we show that glutaminolysis and glutamate-dependent transaminases (TAs) support alpha-ketoglutarate (αKG) levels and are critical regulators of angiogenic response during pathological conditions. Indeed, the endothelial specific blockage of GLS1 impairs ischemic and tumor angiogenesis by suppressing VEGFR2 translation via mTORC1-dependent pathway. Lastly, we discover that ECs catabolized the glutamine-derived glutamate via phosphoserine aminotransferase 1 (PSAT1) as crucial to support VEGFR2 translation. These findings identify glutamine anaplerosis and TA activity as a critical regulator of growth factor receptor translation in normal and pathological angiogenesis. We anticipate our studies to be a starting point for novel anti-angiogenesis approaches based on GLS1/PSAT1 inhibitor treatments to overcome anti-VEGF therapies resistance.
2022-04-22 | PXD022379 | Pride
Project description:Glutamine is a major energy source for tumor cells and blocking glutamine metabolism is being investigated as a promising strategy for cancer therapy. However, the antitumor effect of glutamine blockade in bladder cancer remains unclear, necessitating further investigation. Here, we demonstrated that glutamine metabolism was involved in the malignant progression of bladder cancer. Treatment with the glutamine antagonist 6-Diazo-5-oxo-L-norleucine (DON) inhibited bladder cancer cells in vitro in several ways. In addition, we observed a remarkable inhibition of tumor growth in bladder cancer-bearing mice using JHU083, a prodrug that was designed to prevent DON-induced toxicity. However, the antitumor immune effect of T cells changed from activation to inhibition as the administrated time extended. We found that both in vitro treatment with DON and in vivo prolonged administration of JHU083 led to the upregulation of PD-L1 in bladder cancer cells. Mechanistically, glutamine blockade up-regulates PD-L1 expression in bladder cancer cells by accumulating ROS, subsequently activating the EGFR/ERK/C-Jun signaling pathway. Combinatorial treatment with JHU083 and gefitinib reversed the up-regulation of PD-L1 in bladder cancer cells induced by prolonged glutamine blockade. This reversal resulted in the alleviation of T-cell immunosuppression and a significant improvement in therapeutic outcome. These preclinical findings suggested that broad targeting of glutamine metabolism could represent a viable therapeutic strategy for bladder cancer, with the potential for further enhancement through combined treatment with gefitinib.
2024-08-08 | GSE269520 | GEO
Project description:Cancer cells evade T-cell-mediated killing through poorly understood mechanisms of tumour–immune interactions. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1), mediate T-cell priming and therapeutic efficacy against tumours. Besides pattern recognition receptors (PRRs), how DC functions are shaped by other environmental cues remains incompletely defined. Nutrients are emerging mediators of adaptive immunity, but whether nutrients impact DC function or innate–adaptive cell communication is largely unresolved. Here, we establish glutamine as an intercellular metabolic checkpoint to mediate tumour–cDC1 crosstalk and license cDC1 functionality for activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8+ T-cell immunity, and also overcomes therapeutic resistance to checkpoint blockade and T-cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1 compete for glutamine uptake via transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid for promoting cDC1 function, by signalling via FLCN to impinge upon TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner, and phenocopies SLC38A2 deficiency by abrogating anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1 that underpins tumour immunoevasion, and reveal glutamine acquisition and signalling in cDC1 as limiting events for DC activation and putative targets for cancer treatment.
2023-05-24 | GSE210148 | GEO
Project description:Cancer cells evade T-cell-mediated killing through poorly understood mechanisms of tumour–immune interactions. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1), mediate T-cell priming and therapeutic efficacy against tumours. Besides pattern recognition receptors (PRRs), how DC functions are shaped by other environmental cues remains incompletely defined. Nutrients are emerging mediators of adaptive immunity, but whether nutrients impact DC function or innate–adaptive cell communication is largely unresolved. Here, we establish glutamine as an intercellular metabolic checkpoint to mediate tumour–cDC1 crosstalk and license cDC1 functionality for activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8+ T-cell immunity, and also overcomes therapeutic resistance to checkpoint blockade and T-cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1 compete for glutamine uptake via transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid for promoting cDC1 function, by signalling via FLCN to impinge upon TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner, and phenocopies SLC38A2 deficiency by abrogating anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1 that underpins tumour immunoevasion, and reveal glutamine acquisition and signalling in cDC1 as limiting events for DC activation and putative targets for cancer treatment.
2023-05-24 | GSE210151 | GEO
Project description:Cancer cells evade T-cell-mediated killing through poorly understood mechanisms of tumour–immune interactions. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1), mediate T-cell priming and therapeutic efficacy against tumours. Besides pattern recognition receptors (PRRs), how DC functions are shaped by other environmental cues remains incompletely defined. Nutrients are emerging mediators of adaptive immunity, but whether nutrients impact DC function or innate–adaptive cell communication is largely unresolved. Here, we establish glutamine as an intercellular metabolic checkpoint to mediate tumour–cDC1 crosstalk and license cDC1 functionality for activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8+ T-cell immunity, and also overcomes therapeutic resistance to checkpoint blockade and T-cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1 compete for glutamine uptake via transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid for promoting cDC1 function, by signalling via FLCN to impinge upon TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner, and phenocopies SLC38A2 deficiency by abrogating anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1 that underpins tumour immunoevasion, and reveal glutamine acquisition and signalling in cDC1 as limiting events for DC activation and putative targets for cancer treatment.
2023-05-24 | GSE210153 | GEO
Project description:Cancer cells evade T-cell-mediated killing through poorly understood mechanisms of tumour–immune interactions. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1), mediate T-cell priming and therapeutic efficacy against tumours. Besides pattern recognition receptors (PRRs), how DC functions are shaped by other environmental cues remains incompletely defined. Nutrients are emerging mediators of adaptive immunity, but whether nutrients impact DC function or innate–adaptive cell communication is largely unresolved. Here, we establish glutamine as an intercellular metabolic checkpoint to mediate tumour–cDC1 crosstalk and license cDC1 functionality for activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8+ T-cell immunity, and also overcomes therapeutic resistance to checkpoint blockade and T-cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1 compete for glutamine uptake via transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid for promoting cDC1 function, by signalling via FLCN to impinge upon TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner, and phenocopies SLC38A2 deficiency by abrogating anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1 that underpins tumour immunoevasion, and reveal glutamine acquisition and signalling in cDC1 as limiting events for DC activation and putative targets for cancer treatment.
2023-05-24 | GSE210154 | GEO
Project description:To understand the effects of glutamine deprivation on cell physiology we performed global analysis of gene expression in response to glutamine deprivation. U2OS cells were subjected to glutamine deprivation for 24h followed by RNA extraction and microarray analysis. U2OS cells were plated overnight followed by treatment for 24h with glutamine-containing and glutamine-depleted media. Three biological replicates were assayed for each condition.
2014-07-31 | E-GEOD-59931 | biostudies-arrayexpress
Project description:To understand the effects of glutamine deprivation on cell physiology we performed global analysis of gene expression in response to glutamine deprivation. U2OS cells were subjected to glutamine deprivation for 24h followed by RNA extraction and microarray analysis.
2014-07-31 | GSE59931 | GEO
Project description:To investigate the glutamine inhibition combined with CD47 blockade regulation of ferroptosis in HNSCC. We then performed gene expression profiling analysis using data obtained from RNA-seq of 3 different cells at two time points.
2024-06-30 | GSE228678 | GEO