Metabolic Plasticity in Ovarian Cancer Stem Cells

Abstract

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.

LncRNA ANRIL Regulates Ovarian Cancer Progression and Tumor Stem Cell-Like Characteristics via miR-324-5p/Ran Axis

“…Ovarian cancer is one of the most lethal gynecological malignant owing to the late discovery and high recurrence rate. 16 Resistance to conventional cisplatin therapy is attributed to populations of cancer stem cells that possess stem-like characteristics and high tumorigenicity. 17 It was well documented that the biology of ovarian cancer stem cells and identified various markers and signaling pathways for their self-renewal ability in recent years.…”

Integrative analysis of the common genetic characteristics in ovarian cancer stem cells sorted by multiple approaches

“…To meet the increasing energetic requirements of CSCs, the lipid metabolic pathway can flexibly turn to the other metabolic pathways [26]. CSCs are incredibly reliant on the activity of enzymes involved in lipid metabolism, which engaged in CSCs fate decisions, such as Hippo and Wnt signal pathway [25].…”

“…In our study, we found upregulated genes were enriched in lipid metabolism, which suggested cellular event accumulation of lipids and secondary metabolites. To meet the increasing energetic requirements of CSCs, the lipid metabolic pathway can flexibly turn to the other metabolic pathways [ 26 ]. CSCs are incredibly reliant on the activity of enzymes involved in lipid metabolism, which engaged in CSCs fate decisions, such as Hippo and Wnt signal pathway [ 25 ].…”

Integrative analysis of the common genetic characteristics in ovarian cancer stem cells sorted by multiple approaches

“…In our study, we found upregulated genes were enriched in lipid metabolism, which suggested cellular event accumulation of lipids and secondary metabolites. To meet the increasing energetic requirements of CSCs, the lipid metabolic pathway can exibly turn to the other metabolic pathways [26]. CSCs are incredibly reliant on the activity of enzymes involved in lipid metabolism, which engaged in CSCs fate decisions, such as Hippo and Wnt signal pathway [25].…”