Lipid Desaturation Is a Metabolic Marker and Therapeutic Target of Ovarian Cancer Stem Cells

Abstract

SUMMARY Lack of sensitive single-cell analysis tools has limited the characterization of metabolic activity in cancer stem cells. By hyperspectral stimulated Raman scattering imaging of single living cells and mass spectrometry analysis of extracted lipids, we report here significantly increased levels of unsaturated lipids in ovarian cancer stem cells (CSCs) as compared to non-CSCs. Higher lipid unsaturation levels were also detected in CSC-enriched spheroids compared to monolayer cultures of ovarian cancer cell lines or primary cells. Inhibition of lipid desaturases effectively eliminated CSCs, suppressed sphere formation in vitro, and blocked tumor initiation capacity in vivo. Mechanistically, we demonstrate that NF-κB directly regulates the expression levels of lipid desaturases and that inhibition of desaturases blocks NF-κB signaling. Collectively, our findings reveal that increased lipid unsaturation is a metabolic marker for ovarian CSCs and a target for CSC-specific therapy.

VEGF-A/Neuropilin 1 Pathway Confers Cancer Stemness via Activating Wnt/β-Catenin Axis in Breast Cancer Cells

“…Although many cancer “stemness” markers have been identified, the CSCs-targeting therapies have not been established [2]. Thus, it is urgent to find and target the novel stemness modulators of breast cancer which is a major threat to females worldwide.…”

Unsaturated Fatty Acids Maintain Cancer Cell Stemness

“…In this issue of Cell Stem Cell, Li et al (Li et al, 2016) provide new insights into the interdependency of metabolism and stem cell characteristics by comparing the lipid content and composition of ALDH + CD133 + ovarian CSC with ALDH − CD133 − cancer cells. In an elegantly performed study, the authors show that ovarian cancer stem cells and cancer cells grown as spheroids have a higher ratio of unsaturated to saturated fatty acids, and that this ratio is essential for the cells to retain stemness.…”

Observation-driven inquiry: Raman spectroscopic imaging illuminates cancer lipid metabolism

“…Epitomizing the observation-driven scientific inquiry, Li et al recently deployed a novel Raman spectroscopic imaging technique to uncover lipid unsaturation as a biomarker of ovarian cancer stem cells (CSCs) (8). Following this critical observation with carefully designed experiments, the authors identified a relationship between lipid desaturation, cancer stemness, and the NF-кB signaling pathway.…”

“…Furthermore, multiple earlier publications reported the universal effectiveness of SCD1 inhibition in limiting the growth of cancer cells of various origins including lung, breast, prostate, and colon (12,13). Most significant was the observation that SCD1 and lipid desaturation were required for the formation and growth of cancer spheroids or xenograft tumors (8,12). This observation supports the Editorial Observation-driven inquiry: Raman spectroscopic imaging illuminates cancer lipid metabolism Aurelio Lorico 1 theory of re-activation of de novo lipogenesis in solid tumors as part of cancer metabolic reprogramming.…”

“…Compared to spontaneous Raman microscopy, previously employed by Tirinato et al to visualize lipid droplets in colorectal CSCs (6), hyperspectral SRS microscopy is at least 25,000 times faster. To put this time scale in perspective, a 512 pixels × 512 pixels image could be acquired in less than 1 minute with hyperspectral SRS microscopy versus approximately 364 hours with spontaneous Raman microscopy using reported pixel dwell time of 200 microseconds and 5 seconds, respectively (6,8). Furthermore, single-spectrum SRS imaging has achieved video rate of 20 frames per second.…”