Metabolite systems profiling identifies exploitable weaknesses in retinoblastoma

Sahoo, Swagatika; Kumar, Ranjith Kumar Ravi; Nicolay, Brandon; Mohite, Omkar S.; Sivaraman, Karthikeyan; Khetan, Vikas; Rishi, Pukhraj; Ganesan, Suganeswari; Subramanyan, K.; Raman, Karthik; Miles, Wayne; Elchuri, Sailaja

doi:10.1002/1873-3468.13294

Cited by 14 publications

(20 citation statements)

References 92 publications

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“…We found that advanced Rb was associated with a low expression of glycolytic genes and altered Krebs cycle with a higher propensity for fatty acid metabolism. Our findings are also supported by a recent study that highlighted the role of lipid metabolism in Rb tumors [45]. Furthermore, our global metabolomic profiling of Rb vitreous humor identified a variety of differentially accumulated metabolites that are distinct from the pediatric controls.…”

Section: Discussionsupporting

confidence: 87%

“…This integrated omics analysis of the Rb tumor transcriptome and the vitreous humor metabolome within the human Rb tumor subtypes using the pediatric retina as controls was performed to enrich our understanding of altered gene function with changes in tumor metabolism. Although there have recently been a few reports on alterations in the Rb tumor-associated metabolites [45,46], we found significantly more functional associations between the metabolic targets and the enriched pathways owing to the coordinated samples used for analysis and the use of age-matched pediatric controls. Although we have focused on intraocular advanced and non-advanced retinoblastoma tumors, our findings can be extended to other cancer systems with persistent RB1 mutations.…”

Section: Discussioncontrasting

confidence: 57%

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Integrated Analysis of Cancer Tissue and Vitreous Humor from Retinoblastoma Eyes Reveals Unique Tumor-Specific Metabolic and Cellular Pathways in Advanced and Non-Advanced Tumors

Babu

Mallipatna

et al. 2022

Cells

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Retinoblastoma (Rb) is a pediatric intraocular malignancy that is proposed to originate from maturing cone cell precursors in the developing retina. The molecular mechanisms underlying the biological and clinical behaviors are important to understand in order to improve the management of advanced-stage tumors. While the genetic causes of Rb are known, an integrated understanding of the gene expression and metabolic processes in tumors of human eyes is deficient. By integrating transcriptomic profiling from tumor tissues and metabolomics from tumorous eye vitreous humor samples (with healthy, age-matched pediatric retinae and vitreous samples as controls), we uncover unique functional associations between genes and metabolites. We found distinct gene expression patterns between clinically advanced and non-advanced Rb. Global metabolomic analysis of the vitreous humor of the same Rb eyes revealed distinctly altered metabolites, indicating how tumor metabolism has diverged from healthy pediatric retina. Several key enzymes that are related to cellular energy production, such as hexokinase 1, were found to be reduced in a manner corresponding to altered metabolites; notably, a reduction in pyruvate levels. Similarly, E2F2 was the most significantly elevated E2F family member in our cohort that is part of the cell cycle regulatory circuit. Ectopic expression of the wild-type RB1 gene in the Rb-null Y79 and WERI-Rb1 cells rescued hexokinase 1 expression, while E2F2 levels were repressed. In an additional set of Rb tumor samples and pediatric healthy controls, we further validated differences in the expression of HK1 and E2F2. Through an integrated omics analysis of the transcriptomics and metabolomics of Rb, we uncovered a significantly altered tumor-specific metabolic circuit that reduces its dependence on glycolytic pathways and is governed by Rb1 and HK1.

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Section: Discussionsupporting

confidence: 87%

Section: Discussioncontrasting

confidence: 57%

Integrated Analysis of Cancer Tissue and Vitreous Humor from Retinoblastoma Eyes Reveals Unique Tumor-Specific Metabolic and Cellular Pathways in Advanced and Non-Advanced Tumors

Babu

Mallipatna

et al. 2022

Cells

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“…It is involved in retinal maturation and development [ 80 ]. It has been shown that most Rb tumours are able to generate endogenous GABA via one or several different biosynthetic pathways [ 81 ]. Importantly, GABA is related to cancer cell metastasis and proliferation [ 82 ].…”

Section: Discussionmentioning

confidence: 99%

The regulatory landscape of retinoblastoma: a pathway analysis perspective

et al. 2022

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Retinoblastoma (Rb) is a rare intraocular tumour in early childhood, with an approximate incidence of 1 in 18 000 live births. Experimental studies for Rb are complex due to the challenges associated with obtaining a normal retina to contrast with diseased tissue. In this work, we reanalyse a dataset that contains normal retina samples. We identified the individual genes whose expression is different in Rb in contrast with normal tissue, determined the pathways whose global expression pattern is more distant from the global expression observed in normal tissue, and finally, we identified which transcription factors regulate the highest number of differentially expressed genes (DEGs) and proposed as transcriptional master regulators (TMRs). The enrichment of DEGs in the phototransduction and retrograde endocannabinoid signalling pathways could be associated with abnormal behaviour of the processes leading to cellular differentiation and cellular proliferation. On the other hand, the TMRs nuclear receptor subfamily 5 group A member 2 and hepatocyte nuclear factor 4 gamma are involved in hepatocyte differentiation. Therefore, the enrichment of aberrant expression in these transcription factors could suggest an abnormal retina development that could be involved in Rb origin and progression.

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“…In the past decade, many more cancer-specific models have been reconstructed for liver ( 106 , 149 , 155 , 166 , 173 , 181 ), kidney ( 152 , 154 , 162 , 172 , 172 ), breast ( 103 , 105 , 131 , 145 , 168 ), prostate ( 103 , 104 , 157 , 161 , 162 , 175 ), brain ( 103 , 153 , 167 ), colorectal ( 159 , 170 , 192 ), head and neck ( 148 ), eye ( 147 ), and lung ( 103 , 105 , 131 , 175 ) cancer to generate cancer-specific hypotheses. To compare these various methods for reconstruction of cancer metabolic models, a study benchmarked their predictive performance and consistency ( 91 ), with relevant findings summarized in Table 2 .…”

Section: Genome-scale Modeling Of Cancer Metabolism With Cobra Toolsmentioning

confidence: 99%

Constraint-Based Reconstruction and Analyses of Metabolic Models: Open-Source Python Tools and Applications to Cancer

Lee

Baloni

et al. 2022

Front. Oncol.

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The influence of metabolism on signaling, epigenetic markers, and transcription is highly complex yet important for understanding cancer physiology. Despite the development of high-resolution multi-omics technologies, it is difficult to infer metabolic activity from these indirect measurements. Fortunately, genome-scale metabolic models and constraint-based modeling provide a systems biology framework to investigate the metabolic states and define the genotype-phenotype associations by integrations of multi-omics data. Constraint-Based Reconstruction and Analysis (COBRA) methods are used to build and simulate metabolic networks using mathematical representations of biochemical reactions, gene-protein reaction associations, and physiological and biochemical constraints. These methods have led to advancements in metabolic reconstruction, network analysis, perturbation studies as well as prediction of metabolic state. Most computational tools for performing these analyses are written for MATLAB, a proprietary software. In order to increase accessibility and handle more complex datasets and models, community efforts have started to develop similar open-source tools in Python. To date there is a comprehensive set of tools in Python to perform various flux analyses and visualizations; however, there are still missing algorithms in some key areas. This review summarizes the availability of Python software for several components of COBRA methods and their applications in cancer metabolism. These tools are evolving rapidly and should offer a readily accessible, versatile way to model the intricacies of cancer metabolism for identifying cancer-specific metabolic features that constitute potential drug targets.

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Metabolite systems profiling identifies exploitable weaknesses in retinoblastoma

Cited by 14 publications

References 92 publications

Integrated Analysis of Cancer Tissue and Vitreous Humor from Retinoblastoma Eyes Reveals Unique Tumor-Specific Metabolic and Cellular Pathways in Advanced and Non-Advanced Tumors

Integrated Analysis of Cancer Tissue and Vitreous Humor from Retinoblastoma Eyes Reveals Unique Tumor-Specific Metabolic and Cellular Pathways in Advanced and Non-Advanced Tumors

The regulatory landscape of retinoblastoma: a pathway analysis perspective

Constraint-Based Reconstruction and Analyses of Metabolic Models: Open-Source Python Tools and Applications to Cancer

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