Oncometabolites at the crossroads of genetic, epigenetic and ecological alterations in cancer

Cell Death and Differentiation, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 23, 2024

Abstract By the time a tumor reaches clinical detectability, it contains around 10 8 –10 9 cells. However, during formation, significant cell loss occurs due to death. In some estimates, could take up thousand generations, over ~ 20-year life-span of tumor, reach which would correspond “theoretical” generation ~10 30 These rough calculations indicate that cancers are under negative selection. The fact they thrive implies “evolve”, and their evolutionary trajectories shaped by pressure environment. Evolvability cancer is function its heterogeneity, be at genetic, epigenetic, ecological/microenvironmental levels [1]. principles were summarized in proposed classification Evo (evolutionary) Eco (ecological) indexes used label index addresses cell-autonomous heterogeneity (genetic/epigenetic). describes ecological landscape (non-cell-autonomous) terms hazards survival resources available. reciprocal influence components critical, as can trigger self-sustaining loops shape evolvability [2]. Among various hallmarks [3], metabolic alterations appear unique intersect with both components. This partly because altered metabolism leads accumulation oncometabolites. oncometabolites have traditionally been viewed mediators non-cell-autonomous microenvironment. now increasingly recognized inducers genetic epigenetic modifications. Thus, uniquely positioned crossroads cancer. this review, mechanisms action will summarized, together roles phenotypic evolvability. An perspective impact on natural history presented.

Language: Английский

---

Proteogenomic characterization of high-grade lung neuroendocrine carcinoma deciphers molecular diversity and potential biomarkers of different histological subtypes in Chinese population

Research, Journal Year: 2025, Volume and Issue: 8

Published: Jan. 1, 2025

High-grade lung neuroendocrine carcinomas (Lu-NECs) are clinically refractory malignancies with poor prognosis and limited therapeutic advances. The biological molecular features underlying the histological heterogeneity of Lu-NECs not fully understood. In this study, we present a multi-omics integration whole-exome sequencing deep proteomic profiling in 93 Chinese to establish first comprehensive proteogenomic atlas disease spectrum. Our analyses revealed high degree mutational concordance among subtypes at genomic level; however, distinct profiles enabled clear differentiation subtypes, unveiling subtype-specific related tumor metabolism, immunity, proliferation. Furthermore, RB1 mutations confer divergent prognostic effects through cis- trans- regulation. addition, identified potential protein biomarkers for subtype classification risk stratification, which were validated by immunohistochemistry an independent cohort. This study provides valuable resource insight into Lu-NEC heterogeneity.

Language: Английский

---

Hyperbaric Oxygen Regulates Tumor pH to Boost Copper‐Doped Hydroxyethyl Starch Conjugate Nanoparticles Against Cancer Stem Cells

Exploration, Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

ABSTRACT An extracellular acidic environment and an intracellular mildly alkaline induced by carbonic anhydrase 9 (CA9) play a critical role in self‐renewal, invasion, migration, drug resistance of cancer stem cells (CSCs) within hypoxic solid tumors. Here, we report antitumor strategy leveraging hyperbaric oxygen therapy (HBO) to regulate tumor pH boost hydroxyethyl starch‐doxorubicin‐copper nanoparticles (HHD‐Cu NPs) against CSCs. HBO overcomes hypoxia, downregulates pH‐regulatory proteins such as CA9, leads accumulation metabolites. As result, promotes acidification both CSCs, triggering efficient doxorubicin release the potent copper‐mediated chemical dynamic effect subsequently administered dual‐acid‐responsive HHD‐Cu NPs. The combination with NPs not only eliminates but also inhibits altogether leading inhibition. This study explores new function clinical‐widely used establishes novel for treating CSCs abundant

Language: Английский

---

Metabolic Effects of the Cancer Metastasis Modulator MEMO1

Metabolites, Journal Year: 2025, Volume and Issue: 15(4), P. 277 - 277

Published: April 17, 2025

Background/Objectives: Cancer cells often display altered energy metabolism. In particular, expression levels and activity of the tricarboxylic acid cycle (TCA cycle) enzymes may change in cancer, dysregulation TCA is a frequent hallmark cancer cell MEMO1, modulator metastasis, has been shown to bind iron regulate homeostasis cells. MEMO1 knockout changed mitochondrial morphology content breast Our previous genome-wide analysis genetic interactions across multiple lines revealed that gene sets involved respiration are enriched among gain-of-function interaction partners MEMO1. Based on these findings, we measured metabolite with varying expression. Methods: ShRNA knockdown assay was performed test essentiality key enzymes. metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) MDA-MB-231 (high MEMO1), M67-2 (MEMO1 knockdown), M67-9 knockout) under iron-depleted, basal iron, iron-supplemented conditions. Results: ACO2 OGDH knockdowns inhibit proliferation, indicating an essential role α-Ketoglutarate citrate exhibited inverse relationship expression, increasing significantly regardless availability. contrast, fumarate, malate, glutamate elevated specifically low conditions, suggesting iron-dependent effect. Conclusions: Overall, our results indicate plays regulating manner.

Language: Английский

---

Antioxidative and Cytoprotective Effects of Rosa Roxburghii and Metabolite Changes in Oxidative Stress-Induced HepG2 Cells Following Rosa Roxburghii Intervention

Foods, Journal Year: 2024, Volume and Issue: 13(21), P. 3520 - 3520

Published: Nov. 4, 2024

Rosa Roxburghii (RR), a traditional Chinese medicinal fruit, is rich in bioactive substances that make it potential natural antioxidant resource. This research aimed to study the properties of RR by vitro experiments and through intracellular assessment H2O2-induced HepG2 cells. A non-targeted metabolic analysis was conducted indicate changes extracellular metabolites. Differential metabolites pathways were explored using PCA, PLS-DA, KEGG pathway analysis. The results showed exhibited significant antioxidative property intracellularly. may be achieved scavenging free radicals, increasing activity catalase (CAT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), levels bicinchoninic acid (BCA) while reducing reactive oxygen species (ROS) generation. identified 13 differential intracellularly 7 extracellularly, among which key included D-glucopyranose, D-mannose, fructose, citric acid, malic cholesterol, cholestenone. These primarily regulated glucose-related metabolism, citrate cycle, primary bile biosynthesis findings provide application evidence development resources for functional foods.

Language: Английский

---

From multi-omics to predictive biomarker: AI in tumor microenvironment

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Dec. 23, 2024

In recent years, tumors have emerged as a major global health threat. An increasing number of studies indicate that the production, development, metastasis, and elimination tumor cells are closely related to microenvironment (TME). Advances in artificial intelligence (AI) algorithms, particularly large language models, rapidly propelled research medical field. This review focuses on current state strategies applying AI algorithms metabolism explores expression differences between normal cells. The analysis is conducted from perspectives metabolomics interactions within TME, further examining roles various cytokines. describes potential approaches through which can facilitate metabolic studies, offers valuable perspective for deeper understanding pathological mechanisms tumors.

Language: Английский

---

KDM4 Regulates the Glycolysis of Hemocytes in the Immune Priming of Eriocheir sinensis

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(23), P. 13174 - 13174

Published: Dec. 7, 2024

Immune priming confers a sustained, augmented response of innate immune cells to secondary challenge, process that is characteristically reliant on metabolic reprogramming. Recent evidence suggests histone demethylases play essential roles in the priming, while its regulation role reprogramming remains largely unknown. In present study, concentration glucose was significantly down-regulated hemocytes crab

Language: Английский

---

Methionine-driven YTHDF1 expression facilitates bladder cancer progression by attenuating RIG-I-modulated immune responses and enhancing the eIF5B-PD-L1 axis

Cell Death and Differentiation, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 13, 2024

Abstract The impact of amino acids on tumor immunotherapy is gradually being uncovered. In this study, we screened various essential and non-essential found that methionine enhances mRNA methylation reduced the activation Type I interferon pathway in bladder cancer. Through RNA sequencing, point mutations, MB49 mouse models, single-cell demonstrated high levels elevate expression m 6 A reader YTHDF1, promoting degradation RIG-I, thereby inhibiting RIG-I/MAVS-mediated IFN-I reducing efficacy immunotherapy. Additionally, immunoprecipitation mass spectrometry revealed YTHDF1 binds to eukaryotic translation initiation factor eIF5B, which acts PD-L1 enhance its promote immune evasion. By intravesical administration oncolytic bacteria VNP20009, effectively depleted locally, significantly prolonging survival enhancing cell infiltration differentiation within tumors. Multiplex immunofluorescence assays cancer patients confirmed our findings. Our research elucidates two mechanisms by inhibits proposes a targeted depletion strategy advances while minimizing nutritional patients.

Language: Английский

---