A5086146395- Cancer, Hypoxia, and Metabolism
- Immune Cell Function and Interaction
- Immune cells in cancer
- RNA modifications and cancer
- Epigenetics and DNA Methylation
- Mitochondrial Function and Pathology
- CAR-T cell therapy research
- DNA Repair Mechanisms
- Cancer-related gene regulation
- Cancer Cells and Metastasis
- Cancer-related molecular mechanisms research
- Neuroblastoma Research and Treatments
- Nitric Oxide and Endothelin Effects
- Cancer Research and Treatments
- Cancer-related Molecular Pathways
- Exercise and Physiological Responses
- Metal-Catalyzed Oxygenation Mechanisms
- Nanoplatforms for cancer theranostics
- Cancer Immunotherapy and Biomarkers
- Adipose Tissue and Metabolism
- T-cell and B-cell Immunology
- Neuroinflammation and Neurodegeneration Mechanisms
- Fungal and yeast genetics research
- Franz Kafka Literary Studies
- Geographies of human-animal interactions
Sanquin
2022-2024
University of Amsterdam
2022-2024
University of Cambridge
2019-2024
Amsterdam University Medical Centers
2024
Oncode Institute
2022-2024
Karolinska Institutet
2019-2023
CRUK/MRC Oxford Institute for Radiation Oncology
2013-2021
University of Oxford
2013-2021
Academy of Athens
2012-2020
Biomedical Research Foundation of the Academy of Athens
2020
Restoration of hypoxia-induced apoptosis in tumors harboring p53 mutations has been proposed as a potential therapeutic strategy; however, the transcriptional targets that mediate p53-dependent remain elusive. Here, we demonstrated is reliant on DNA-binding and transactivation domains but not acetylation sites K120 K164, which, contrast, are essential for DNA damage-induced, apoptosis. Evaluation transcripts multiple cell lines identified group genes hypoxia-inducible proapoptotic p53,...
Oxygenation levels are a determinative factor in T cell function. Here, we describe how oxygen tensions sensed by mouse and human cells at the moment of activation act to persistently modulate both differentiation We found that protocol CAR-T generation, 24 hr low during initial CD8+ priming is sufficient enhance antitumour cytotoxicity preclinical model. This case even when subsequently cultured under high prior adoptive transfer. Increased hypoxia-inducible transcription (HIF) expression...
T cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of α-ketoglutarate-dependent dioxygenases, others, post-translational modification lysines important targets. We show here that glutarate, a product amino acid catabolism, has the capacity to do both, potent effects on differentiation. found glutarate exerts those both dioxygenase inhibition, direct regulation metabolism via glutarylation pyruvate dehydrogenase E2 subunit....
Cells exposed to hypoxia experience replication stress but do not accumulate DNA damage, suggesting sustained replication. Ribonucleotide reductase (RNR) is the only enzyme capable of de novo synthesis deoxyribonucleotide triphosphates (dNTPs). However, oxygen an essential cofactor for mammalian RNR (RRM1/RRM2 and RRM1/RRM2B), leading us question source dNTPs in hypoxia. Here, we show that RRM1/RRM2B retaining activity therefore favored over RRM1/RRM2 order preserve ongoing avoid...
CD8+ T cells infiltrate virtually every tissue to find and destroy infected or mutated cells. They often traverse varying oxygen levels nutrient-deprived microenvironments. High glycolytic activity in local tissues can result significant exposure of cytotoxic the lactate metabolite. Lactate has been known act as an immunosuppressor, at least part due its association with acidosis.To dissect role anion, independently pH, we performed phenotypical metabolic assays, high-throughput RNA...
Abstract Adoptive transfer of antitumor cytotoxic T cells is an emerging form cancer immunotherapy. A key challenge to expanding the utility adoptive cell therapies how enhance survival and function transferred cells. Immune-cell requires adaptation different microenvironments particularly hypoxic milieu solid tumors. The hypoxia-inducible factor (HIF) transcription factors are essential aspect this adaptation. In study, we undertook experiments define structural determinants HIF that...
Abstract Tumour hypoxia is associated with poor patient prognosis and therapy resistance. A unique transcriptional response initiated by which includes the rapid activation of numerous transcription factors in a background reduced global transcription. Here, we show that biological to accumulation R-loops induction RNA/DNA helicase SETX. In absence hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, replication rates decrease. Therefore, suggesting that, SETX plays role...
Targeting T cell metabolism is an established method of immunomodulation. Following activation, cells engage distinct metabolic programs leading to the uptake and processing nutrients that determine proliferation differentiation. Redirection fate by modulation these has been shown boost or suppress immune responses
Abstract Cancer immunotherapy is advancing rapidly and gene-modified T cells expressing chimeric antigen receptors (CARs) show particular promise. A challenge of CAR-T cell therapy that the ex vivo–generated become exhausted during expansion in culture, do not persist when transferred back to patients. It has clear naive memory CD8 perform better than total T-cell populations because expansion, antitumor activity, persistence, which are necessary features for therapeutic success prevention...
2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and readily detected in tissues healthy individuals. 2HG found two enantiomeric forms: S-2HG R-2HG. Here, we investigate differential roles these enantiomers cluster differentiation (CD)8+ T cell biology, where find they have highly divergent effects on proliferation, differentiation, function. We show here an analysis structural determinants that likely underlie specific α-ketoglutarate (αKG)-dependent enzymes....
We have functionally characterized the four Saccharomyces cerevisiae (Sc) Jen1 homologues of Debaryomyces hansenii (Dh) by heterologous expression in S. cerevisiae. cells display mediated transport for uptake lactate, acetate, succinate and malate. DHJEN genes was detected RT-PCR all carbon sources assayed, namely succinate, citrate, glycerol glucose. The W303-1A jen1Δ ady2Δ strain demonstrated that D. JEN encode carboxylate transporters. DH27 gene encodes an acetate transporter (Km 0.94 ±...
Abstract Exercise has a range of effects on metabolism. In animal models, repeated exertion reduces malignant tumour progression, and clinically, exercise can improve outcome for cancer patients. The etiology the effect progression is unclear, as are cellular actors involved. We show here that exercise-induced reduction in growth dependent CD8+ T cells lactate, which produced at high levels during exertion, increases proliferative capacity cytotoxicity cells. found elevated lactate used fuel...
How tumor cells adapt and survive under hypoxia significantly impacts patient prognosis. We recently demonstrated that the oxygen-requiring ribonucleotide reductase (RNR) enzyme, which provides with deoxyribonucleotides, responds to limited oxygen availability by switching small subunits from RRM2 RRM2B. This property of RNR is essential for hypoxic cell viability therefore contributes most aggressive therapy-resistant fraction tumors.
Abstract T cell function is influenced by several metabolites; some acting through enzymatic inhibition of α-KG-dependent dioxygenases (αKGDDs), others, post-translational modification lysines in important targets. We show here that glutarate, a product amino acid catabolism, has the capacity to do both, with effects on and differentiation. Glutarate exerts those αKGDD direct regulation metabolism via pyruvate dehydrogenase E2 subunit. Diethyl-glutarate, cell-permeable form alters CD8 +...
Exercise has a wide range of systemic effects. In animal models, repeated exertion reduces malignant tumor progression, and clinically, exercise can improve outcome for cancer patients. The etiology the effect on progression is unclear, as are cellular actors involved. We show here that exercise-induced reduction in growth dependent CD8+ T cells lactate, which produced at high levels during exertion, increases proliferative capacity cytotoxicity cells. found elevated lactate used fuel cell...
T cells must adapt to variations in tissue microenvironments; these adaptations include the degree of oxygen availability. The hypoxia-inducible factor (HIF) transcription factors control much this adaptation, and thus regulate many aspects cell activation function. HIFs are turn regulated by oxygen-dependent hydroxylases: both prolyl hydroxylases (PHDs) which interact with VHL tumour suppressor HIF turnover, asparaginyl hydroxylase known as Factor inhibiting (FIH), modulates transcriptional...
<title>Abstract</title> CD8<sup>+</sup> T cells can rapidly produce effector molecules following activation. This activation triggers fast changes in gene expression that rely on control of mRNA levels via multiple transcriptional and post-transcriptional mechanisms, including RNA modifications. N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) is an abundant modification promotes the decay messenger RNAs cytosol. How recognition m<sup>6</sup>A sites integrated with other regulatory mechanisms...
Nitric oxide (NO) is a signaling molecule produced by NO synthases (NOS1-3) to control processes such as neurotransmission, vascular permeability, and immune function. Although myeloid cell-derived has been shown suppress T-cell responses, the role of synthesis in T cells themselves not well understood. Here, we showed that significant amounts were synthesized human murine CD8+ following activation. Tumor growth was significantly accelerated cell-specific, Nos2-null mouse model. Genetic...