Lipid Droplets Define a Sub-Population of Breast Cancer Stem Cells

Abstract

Tumor recurrence is now the leading cause of breast cancer-related death. These recurrences are believed to arise from residual cancer stem cells that survive initial therapeutic intervention. Therefore, a comprehensive understanding of cancer stem cell biology is needed to generate more effective therapies. Here we investigate the association between dysregulation of lipid metabolism and breast cancer stem cells. Focusing specifically on lipid droplets, we found that the lipid droplet number correlates with stemness in a panel of breast cell lines. Using a flow cytometry-based method developed for this study, we establish a means to isolate cells with augmented lipid droplet loads from total populations and show that they are enriched in cancer stem cells. Furthermore, pharmacological targeting of fatty acid metabolism reveals a metabolic addiction in a subset of cell lines. Our results highlight a key role for the lipid metabolism in the maintenance of the breast cancer stem cell pool, and as such, suggest it as a potential therapeutic target.

CD44 in Ovarian Cancer Progression and Therapy Resistance—A Critical Role for STAT3

“…The CD36 overexpressing CD44+ cells possess an increased metastasis-initiating potential, which is highly dependent on the absorbed fatty acids as an energy source compared to the low CD36 non-metastatic counterparts ( 224 ). Also, CD44+ breast CSCs not only show high lipid droplet accumulation ( 225 ), but also require FAO for maintenance of self-renewal and chemoresistance through JAK/STAT3 mediated induction of CPT1B, another isoform of CPT1, as recently demonstrated by our group ( 226 ). Similarly, CD44+ CSCs derived from ovarian cancer patients show both upregulated glucose uptake and the expression of key genes associated with OXPHOS and FAO ( 227 ).…”

PPARα-Selective Antagonist GW6471 Inhibits Cell Growth in Breast Cancer Stem Cells Inducing Energy Imbalance and Metabolic Stress

“…Previous investigations showed higher mevalonate synthesis in tumor cells as a consequence of improved levels and catalytic efficiency of 3′-hydroxy-3′-methylglutaryl-CoA reductase (HMGCR): the rate-limiting enzyme of cholesterol biosynthesis that catalyzes the formation of MVA [ 49 ]. Moreover, in breast cancer, a significant increase in lipid droplets with malignancy was reported [ 38 , 50 ]. In our experimental conditions, PPARα inhibition determined a substantial effect on cell viability and proliferation, probably related to the significant impact on energetic metabolism, including the altered mevalonate pathway and a marked impairment of lipid and glucose metabolism.…”

Cancer Stem Cell Characteristics by Network Analysis of Transcriptome Data Stemness Indices in Breast Carcinoma

“…Recent evidence suggests that strategies that induce differentiation of CSCs could make a difference in the eradication of tumor cells, which means suppressing certain transcription factors could affect tumor recurrence [ 21 ]. Breast cancer stem cell pools are associated with many elements, of which lipid metabolism cannot be ignored [ 22 ]. Typical BC therapies include surgery, radiation, and chemotherapy.…”

“…Typical BC therapies include surgery, radiation, and chemotherapy. However, stem cells maintain extremely high reproduction and migration rates; therapies that do not target stem cells are linked with higher tumor recurrence rates [ 22 ]. This study sheds new light on screening potential upstream targeting genes.…”