Metabolic clogging of mannose triggers genomic instability via dNTP loss in human cancer cells DOI Creative Commons
Yoichiro Harada, Yu Mizote, Takehiro Suzuki

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Oct. 17, 2022

Abstract Mannose has anti-cancer activity that inhibits cell proliferation and enhances the efficacy of chemotherapy. How mannose exerts its activity, however, remains poorly understood. Here, using genetically engineered human cancer cells permit precise control metabolic flux, we demonstrate large influx exceeding capacity induced remodeling, leading to generation slow-cycling with limited deoxyribonucleoside triphosphates (dNTPs). This remodeling impaired dormant origin firing required rescue stalled forks by cisplatin, thus exacerbating replication stress. Importantly, pharmacological inhibition de novo dNTP biosynthesis was sufficient retard cycle progression, sensitize inhibit firing, suggesting loss-induced genomic instability as a central mechanism for mannose.

Language: Английский

Metabolic clogging of mannose triggers dNTP loss and genomic instability in human cancer cells DOI Creative Commons
Yoichiro Harada, Yu Mizote, Takehiro Suzuki

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: July 18, 2023

Mannose has anticancer activity that inhibits cell proliferation and enhances the efficacy of chemotherapy. How mannose exerts its activity, however, remains poorly understood. Here, using genetically engineered human cancer cells permit precise control metabolic flux, we demonstrate large influx exceeding capacity induced remodeling, leading to generation slow-cycling with limited deoxyribonucleoside triphosphates (dNTPs). This remodeling impaired dormant origin firing required rescue stalled forks by cisplatin, thus exacerbating replication stress. Importantly, pharmacological inhibition de novo dNTP biosynthesis was sufficient retard cycle progression, sensitize inhibit firing, suggesting loss-induced genomic instability as a central mechanism for mannose.

Language: Английский

Citations

10
The main sources of molecular organization in the cell. Atlas of self-organized and self-regulated dynamic biostructures DOI
Ildefonso M. De la Fuente, Jesús M. Cortés, Iker Malaina

et al.

Progress in Biophysics and Molecular Biology, Journal Year: 2025, Volume and Issue: 195, P. 167 - 191

Published: Jan. 11, 2025

Language: Английский

Citations

0
Understanding metabolic plasticity at single cell resolution DOI Creative Commons

Christina C. Abbate,

Jason Hu, John G. Albeck

et al.

Essays in Biochemistry, Journal Year: 2024, Volume and Issue: 68(3), P. 273 - 281

Published: Oct. 28, 2024

Abstract It is increasingly clear that cellular metabolic function varies not just between cells of different tissues, but also within tissues and cell types. In this essay, we envision how differences in central carbon metabolism arise from multiple sources, including the cycle, circadian rhythms, intrinsic cycles, others. We discuss compare methods enable such variation to be detected, single-cell metabolomics RNA-sequencing. pay particular attention biosensors for AMPK metabolites, which when used combination with perturbations, provide evidence variance function.

Language: Английский

Citations

2
Combining denoising of RNA-seq data and flux balance analysis for cluster analysis of single cells DOI Creative Commons
Bruno G. Galuzzi, Marco Vanoni, Chiara Damiani

et al.

BMC Bioinformatics, Journal Year: 2022, Volume and Issue: 23(S6)

Published: Oct. 25, 2022

Abstract Background Sophisticated methods to properly pre-process and analyze the increasing collection of single-cell RNA sequencing (scRNA-seq) data are increasingly being developed. On contrary, best practices integrate these into metabolic networks, aiming at describing phenotypes within a heterogeneous cell population, have been poorly investigated. In this regard, critical factor is presence false zero values in reactions essential for fundamental function, such as biomass or energy production. Here, we investigate role denoising strategies mitigating problem. Methods We applied state-of-the-art - namely MAGIC, ENHANCE, SAVER on three public scRNA-seq datasets. then associated flux distribution with every single by embedding its noise-free transcriptomics profile constraints optimization core model. Finally, used obtained optimal fluxes features cluster analysis. compared results different techniques, without use denoising. also investigated possibility applying directly Reaction Activity Scores, which extracted from read counts, rather than counts. Results show that improves clustering cells. illustrate restores important properties, correlation between cycle phase accumulation, RAS scores belonging same pathway. MAGIC performs better ENHANCE SAVER, that, matrix could be an effective alternative removing reactions. Conclusions Our indicate including pre-processing operation represents milestone Flux Balance Analysis simulations perform analysis focus phenotypes.

Language: Английский

Citations

10
A mathematical model for pancreatic cancer during intraepithelial neoplasia DOI Creative Commons

Joshua Briones-Andrade,

Guillermo Ramı́rez-Santiago, J. Roberto Romero-Arias

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 17, 2024

Abstract Cancer is the result of complex interactions intrinsic and extrinsic cell processes, which promote sustained proliferation, resistance to apoptosis, reprogramming reorganization. To understand evolution any type cancer it necessary role microenvironmental conditions impact some molecular complexes mechanisms on certain signalling pathways. As in most quantitative models, understanding early onset requires a multiscale analysis cellular microenvironment. In this paper we analyse model pancreatic adenocarcinoma by modelling microenvironment through elastic their intercellular communication mechanisms, such as growth factors cytokines. We focus low-grade dysplasia (PanIN 1) moderate 2) stages adenocarcinoma. end propose gene regulatory network associated with processes proliferation apoptosis cells its kinetics terms delayed differential equations mimic development. Likewise, couple cycle spatial distribution transport show that triggered inflammatory processes. oncogene RAS may be an important target develop anti-inflammatory strategies limit emergence more aggressive adenocarcinomas.

Language: Английский

Citations

1
Glucose to lactate shift reprograms CDK-dependent mitotic decisions and its communication with MAPK Sty1 in Schizosaccharomyces pombe DOI Creative Commons
Priyanka Sarkar, S. Misra, Agamani Ghosal

et al.

Biology Open, Journal Year: 2023, Volume and Issue: 12(10)

Published: Oct. 3, 2023

Cell cycle regulation in response to biochemical cues is a fundamental event associated with many diseases. The of such responses complex metabolic environments poorly understood. This study reveals unknown aspects the cell division Schizosaccharomyces pombe. We show that changing carbon source from glucose lactic acid alters functions cyclin-dependent kinase (CDK) Cdc2 and mitogen-activated protein (MAPK) Sty1, leading unanticipated outcomes behavior fate cells. Functional communication Sty1 known be an integral part cellular aberrant activity S. Our results cross-talk between consequent Sty1-dependent activity, appears compromised relationship mitotic timing also reversed presence lactate. status cells under these conditions important determinant altered molecular mentioned above as well

Language: Английский

Citations

1
Editorial overview: The metabolic network DOI
Sarah‐Maria Fendt, Markus Ralser

Current Opinion in Systems Biology, Journal Year: 2022, Volume and Issue: 31, P. 100432 - 100432

Published: June 28, 2022

Language: Английский

Citations

0
Metabolic clogging of mannose triggers genomic instability via dNTP loss in human cancer cells DOI Creative Commons
Yoichiro Harada, Yu Mizote, Takehiro Suzuki

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Oct. 17, 2022

Abstract Mannose has anti-cancer activity that inhibits cell proliferation and enhances the efficacy of chemotherapy. How mannose exerts its activity, however, remains poorly understood. Here, using genetically engineered human cancer cells permit precise control metabolic flux, we demonstrate large influx exceeding capacity induced remodeling, leading to generation slow-cycling with limited deoxyribonucleoside triphosphates (dNTPs). This remodeling impaired dormant origin firing required rescue stalled forks by cisplatin, thus exacerbating replication stress. Importantly, pharmacological inhibition de novo dNTP biosynthesis was sufficient retard cycle progression, sensitize inhibit firing, suggesting loss-induced genomic instability as a central mechanism for mannose.

Language: Английский

Citations

0