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The Role of Metabolic Plasticity in Blood and Brain Stem Cell Pathophysiology.

ABSTRACT: Our understanding of intratumoral heterogeneity in cancer continues to evolve, with current models incorporating single-cell signatures to explore cell-cell interactions and differentiation state. The transition between stem and differentiation states in nonneoplastic cells requires metabolic plasticity, and this plasticity is increasingly recognized to play a central role in cancer biology. The insights from hematopoietic and neural stem cell differentiation pathways were used to identify cancer stem cells in leukemia and gliomas. Similarly, defining metabolic heterogeneity and fuel-switching signals in nonneoplastic stem cells may also give important insights into the corresponding molecular mechanisms controlling metabolic plasticity in cancer. These advances are important, because metabolic adaptation to anticancer therapeutics is rooted in this inherent metabolic plasticity and is a therapeutic challenge to be overcome.

SUBMITTER: Libby CJ

PROVIDER: S-EPMC7153784 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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The Role of Metabolic Plasticity in Blood and Brain Stem Cell Pathophysiology.

Libby Catherine J CJ McConathy Jonathan J Darley-Usmar Victor V Hjelmeland Anita B AB

Cancer research 20191001 1

Our understanding of intratumoral heterogeneity in cancer continues to evolve, with current models incorporating single-cell signatures to explore cell-cell interactions and differentiation state. The transition between stem and differentiation states in nonneoplastic cells requires metabolic plasticity, and this plasticity is increasingly recognized to play a central role in cancer biology. The insights from hematopoietic and neural stem cell differentiation pathways were used to identify cance ...[more]

PMID: 31575548

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Project description:Ovarian Cancer is the fifth most common cancer in females and remains the most lethal gynecological malignancy as most patients are diagnosed at late stages of the disease. Despite initial responses to therapy, recurrence of chemo-resistant disease is common. The presence of residual cancer stem cells (CSCs) with the unique ability to adapt to several metabolic and signaling pathways represents a major challenge in developing novel targeted therapies. The objective of this study is to investigate the transcripts of putative ovarian cancer stem cell (OCSC) markers in correlation with transcripts of receptors, transporters, and enzymes of the energy generating metabolic pathways involved in high grade serous ovarian cancer (HGSOC). We conducted correlative analysis in data downloaded from The Cancer Genome Atlas (TCGA), studies of experimental OCSCs and their parental lines from Gene Expression Omnibus (GEO), and Cancer Cell Line Encyclopedia (CCLE). We found positive correlations between the transcripts of OCSC markers, specifically CD44, and glycolytic markers. TCGA datasets revealed that NOTCH1, CD133, CD44, CD24, and ALDH1A1, positively and significantly correlated with tricarboxylic acid cycle (TCA) enzymes. OVCAR3-OCSCs (cancer stem cells derived from a well-established epithelial ovarian cancer cell line) exhibited enrichment of the electron transport chain (ETC) mainly in complexes I, III, IV, and V, further supporting reliance on the oxidative phosphorylation (OXPHOS) phenotype. OVCAR3-OCSCs also exhibited significant increase in CD36, ACACA, SCD, and CPT1A, with CD44, CD133, and ALDH1A1 exhibiting positive correlations with lipid metabolic enzymes. TCGA data show positive correlations between OCSC markers and glutamine metabolism enzymes, whereas in OCSC experimental models of GSE64999, GSE28799, and CCLE, the number of positive and negative correlations observed was significantly lower and was different between model systems. Appropriate integration and validation of data model systems with those in patients' specimens is needed not only to bridge our knowledge gap of metabolic programing of OCSCs, but also in designing novel strategies to target the metabolic plasticity of dormant, resistant, and CSCs.

Dataset Information

The Role of Metabolic Plasticity in Blood and Brain Stem Cell Pathophysiology.

Publications

The Role of Metabolic Plasticity in Blood and Brain Stem Cell Pathophysiology.

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