Dataset Information

Drug-Tolerant Idling Melanoma Cells Exhibit Theory-Predicted Metabolic Low-Low Phenotype.

ABSTRACT: Cancer cells adjust their metabolic profiles to evade treatment. Metabolic adaptation is complex and hence better understood by an integrated theoretical-experimental approach. Using a minimal kinetic model, we predicted a previously undescribed Low/Low (L/L) phenotype, characterized by low oxidative phosphorylation (OXPHOS) and low glycolysis. Here, we report that L/L metabolism is observed in BRAF-mutated melanoma cells that enter a drug-tolerant "idling state" upon long-term MAPK inhibition (MAPKi). Consistently, using publicly available RNA-sequencing data of both cell lines and patient samples, we show that melanoma cells decrease their glycolysis and/or OXPHOS activity upon MAPKi and converge toward the L/L phenotype. L/L metabolism is unfavorable for tumor growth, yet supports successful cell division at ~50% rate. Thus, L/L drug-tolerant idling cells are a reservoir for accumulating mutations responsible for relapse, and it should be considered as a target subpopulation for improving MAPKi outcomes in melanoma treatment.

SUBMITTER: Jia D

PROVIDER: S-EPMC7457027 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Drug-Tolerant Idling Melanoma Cells Exhibit Theory-Predicted Metabolic Low-Low Phenotype.

Jia Dongya D Paudel B Bishal BB Hayford Corey E CE Hardeman Keisha N KN Levine Herbert H Onuchic José N JN Quaranta Vito V

Frontiers in oncology 20200814

Cancer cells adjust their metabolic profiles to evade treatment. Metabolic adaptation is complex and hence better understood by an integrated theoretical-experimental approach. Using a minimal kinetic model, we predicted a previously undescribed Low/Low (L/L) phenotype, characterized by low oxidative phosphorylation (OXPHOS) and low glycolysis. Here, we report that L/L metabolism is observed in <i>BRAF</i>-mutated melanoma cells that enter a drug-tolerant "idling state" upon long-term MAPK inhib ...[more]

PMID: 32923395

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Project description:Celiac disease (CD) is an autoimmune disease caused by a loss of gluten tolerance in genetically predisposed individuals. While 30%-40% of people possess the predisposing alleles, only 1%-2% are diagnosed with CD, suggesting that environmental factors are involved in disease pathogenesis. To determine an association between pediatric CD and the gut microbiome, we analyzed fecal samples from a prospective cohort study (ABIS). These samples were collected from children who later developed CD (CD progressors) and age-matched healthy children (at ages 1, 2.5, and 5) with similar HLA genotypes, breastfeeding durations, and gluten exposure times. We previously reported gut microbiome differences at ages 2.5 and 5 in this cohort; here, we present findings from samples collected at age 1 (n = 5). We identified 14 ASVs differing significantly between CD progressors and controls, including taxa linked to CD pathogenesis. CD progressors had increased Firmicutes and higher alpha diversity in IgA- bacteria. Using PICRUSt, we analyzed metabolic pathways enriched in CD progressors compared to controls at ages 1, 2.5, and 5 (n = 5-16), revealing enriched inflammatory and pathogenic pathways potentially contributing to CD-related immune dysregulation. While results are based on the primary EdgeR analysis, we also applied a non-parametric method of statistical analysis, reporting those results with supplementary figures. In conclusion, our findings suggest distinct metabolic pathways enriched in the gut microbiome of CD progressors years before diagnosis, which could inform targeted therapeutics for CD. As discussed in the limitations section, this small pilot study should be replicated with larger sample sizes for broader generalization.ImportanceWe analyzed gut microbiome data from children who later developed celiac disease (CD progressors) compared to healthy children in the first 5 years of life. Using fecal samples corresponding to the three phases of gut microbiome development, we uncovered enriched functional microbial pathways in CD progressors at age 1. Some of these pathways, implicated in bacterial pathogenesis, microbiota modulation, and inflammation, have been correlated with CD. We also identified taxa in CD progressors at age 1 including Lachnospiraceae, Alistipes, and Bifidobacterium dentium that were previously associated with CD. These findings suggest a potential role for these taxa and enriched pathways in pediatric CD onset years before diagnosis, highlighting potential for early interventions. While the findings of this exploratory study should be validated with larger sample sizes, our study suggests microbial metabolic pathways related to CD onset, enhancing our understanding of CD pathogenesis and the role of gut microbiome-mediated early alterations.

Dataset Information

Drug-Tolerant Idling Melanoma Cells Exhibit Theory-Predicted Metabolic Low-Low Phenotype.

Publications

Drug-Tolerant Idling Melanoma Cells Exhibit Theory-Predicted Metabolic Low-Low Phenotype.

Similar Datasets

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