Exploring the metabolic landscape of pancreatic ductal adenocarcinoma cells using genome-scale metabolic modeling

Islam, Mohammad Mazharul; Goertzen, Andrea; Singh, Pankaj K.; Saha, Rajib

doi:10.1016/j.isci.2022.104483

Cited by 6 publications

(3 citation statements)

References 142 publications

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“…Other drugs for non-oncological use have shown off-label efficacy in PDAC, modulating proliferative arrest [ 176 ]. When drug targets, such as GLUT-1 , were knocked out, a strong growth-inhibiting effect on PDAC biomass was observed, resulting in a no-growth phenotype [ 177 ].…”

Section: Clinical Perspectivesmentioning

confidence: 99%

Metabolic Pathways as a Novel Landscape in Pancreatic Ductal Adenocarcinoma

Ali

Chianese

Papulino

et al. 2022

Cancers

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Metabolism plays a fundamental role in both human physiology and pathology, including pancreatic ductal adenocarcinoma (PDAC) and other tumors. Anabolic and catabolic processes do not only have energetic implications but are tightly associated with other cellular activities, such as DNA duplication, redox reactions, and cell homeostasis. PDAC displays a marked metabolic phenotype and the observed reduction in tumor growth induced by calorie restriction with in vivo models supports the crucial role of metabolism in this cancer type. The aggressiveness of PDAC might, therefore, be reduced by interventions on bioenergetic circuits. In this review, we describe the main metabolic mechanisms involved in PDAC growth and the biological features that may favor its onset and progression within an immunometabolic context. We also discuss the need to bridge the gap between basic research and clinical practice in order to offer alternative therapeutic approaches for PDAC patients in the more immediate future.

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Section: Clinical Perspectivesmentioning

confidence: 99%

Metabolic Pathways as a Novel Landscape in Pancreatic Ductal Adenocarcinoma

Ali

Chianese

Papulino

et al. 2022

Cancers

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“…Systems biology has been proven to be very useful for pragmatic modelling and theoretical exploration of complex biological systems (21). By the integration of high-throughput omics data (metabolomics, proteomics, or transcriptomics), the reconstruction of human GSM models of pancreatic cancer (22), tuberculosis (23), obesity and diabetes's (24), neurodegenerative diseases (25) has led to discovery of novel therapeutic targets and better understanding of the metabolic shifts.…”

Section: Introductionmentioning

confidence: 99%

Dissecting Metabolic Landscape of Alveolar Macrophage

Malla,

Sajeevan,

Acharya

et al. 2023

Preprint

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The highly plastic nature of Alveolar Macrophage (AM) plays a crucial role in the defense against inhaled particulates and pathogens in the lungs. Depending upon the signal, AM acquires either classically activated M1 phenotype or alternatively activated M2 phenotype. These phenotypes have specific functions and unique metabolic traits such as upregulated glycolysis and pentose phosphate pathway in M1 phase and enhanced oxidative phosphorylation and tricarboxylic acid cycle during M2 phase that help maintain the sterility of the lungs. In this study, we investigate the metabolic shift in the activated phases of AM (M1 and M2 phase) and highlight the roles of pathways other than the typical players of central carbon metabolism. Pathogenesis is a complex and elongated process where the heightened requirement for energy is matched by metabolic shifts that supplement immune response and maintain homeostasis. The first step of pathogenesis is fever; however, analyzing the role of physical parameters such as temperature is challenging. Here, we observe the effect of an increase in temperature on pathways such as glycolysis, pentose phosphate pathway, oxidative phosphorylation, tricarboxylic acid cycle, amino acid metabolism, and leukotriene metabolism. We report the role of temperature as a catalyst to the immune response of the cell. The activity of pathways such as pyruvate metabolism, arachidonic acid metabolism, chondroitin/heparan sulfate biosynthesis, and heparan sulfate degradation are found to be important driving forces in the M1/M2 phenotype. We have also identified a list of 34 reactions such as nitric oxide production from arginine and the conversion of glycogenin to UDP which play major roles in the metabolic models and prompt the shift of the M2 phenotype to M1 and vice versa. In future, these reactions could further be probed as major contributors in designing effective therapeutic targets against severe respiratory diseases.Author SummaryAlveolar macrophage (AM) is highly plastic in nature and has a wide range of functions including invasion/killing of bacteria to maintaining the homeostasis in the lungs. The regulatory mechanism involved in the alveolar macrophage polarization is essential to fight against severe respiratory conditions (pathogens and particulates). Over the years, experiments on mouse/rat models have been used to draw insightful inferences. However, recent advances have highlighted the lack of transmission from non-human models to successfulin vivohuman experiments. Hence using genome-scale metabolic (GSM) models to understand the unique metabolic traits of human alveolar macrophages and comprehend the complex metabolic underpinnings that govern the polarization can lead to novel therapeutic strategies. The GSM models of AMs thus far, has not incorporated the activated phases of AM. Here, we aim to exhaustively dissect the metabolic landscape and capabilities of AM in its healthy and activated stages. We carefully explore the changes in reaction fluxes under each of the conditions to understand the role and function of all the pathways with special attention to pathways away from central carbon metabolism. Understanding the characteristics of each phase of AM has applications that could help improve the therapeutic approaches against respiratory conditions.

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“…Genome-scale metabolic models (GSMMs), which connect metabolic genes, proteins, and metabolites based on gene-protein-reaction association and stoichiometric matrix, are practical systems biology tools for describing cellular metabolism 7 . Several studies have integrated the gene expression data into GSMMs to get valuable insights into understanding human diseases and infections [8][9][10][11][12][13] and the knockout effects of genes 14 . Recent studies have utilised GSMM to reconstruct personalised organ-specific metabolic models to address the V2F challenge 15,16 .…”

Section: Introductionmentioning

confidence: 99%

Unravelling variant-to-function relationships in sporulation efficiency through integrative analysis of SNP-specific gene expression networks and metabolic models

Sasikumar,

Pavan Kumar,

Bhatt

et al. 2023

Preprint

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Elucidating genotype-phenotype or variant-to-function relationships remains a pivotal challenge in genetics. Specifically, understanding how genetic interactions among causal quantitative trait nucleotides (QTNs) drive phenotypic variation remains to be determined. Employing genome-scale metabolic modelling, we analysed the metabolic consequences of four causal QTNs, individually and in all combinations, responsible for modulating sporulation efficiency in yeast. Differential gene expression and network analysis revealed QTN interactions dependent changes in the connectivity of crucial metabolic regulators. Furthermore, QTN-specific metabolic models and genome-scale differential flux analysis pinpointed variations in flux across multiple metabolic pathways that could explain the observed sporulation efficiency differences. Finally, the differential regulation of the pentose phosphate pathway in specific QTN combinations suggested autophagy as a pentose phosphate pathway-dependent compensatory mechanism for yeast sporulation. Our study contributes to the evolving functional understanding of variants, providing insightful information into the mechanisms governing phenotypic variation.

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Exploring the metabolic landscape of pancreatic ductal adenocarcinoma cells using genome-scale metabolic modeling

Cited by 6 publications

References 142 publications

Metabolic Pathways as a Novel Landscape in Pancreatic Ductal Adenocarcinoma

Metabolic Pathways as a Novel Landscape in Pancreatic Ductal Adenocarcinoma

Dissecting Metabolic Landscape of Alveolar Macrophage

Unravelling variant-to-function relationships in sporulation efficiency through integrative analysis of SNP-specific gene expression networks and metabolic models

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