Abstract AP21: LIPID DESATURATION IS A METABOLIC MARKER AND THERAPEUTIC TARGET OF OVARIAN CANCER STEM CELLS

Abstract

OBJECTIVES: Lack of sensitive single-cell analysis tools has limited the characterization of the metabolic activity of cancer stem cells (CSCs). The objectives of this study were to identify and target metabolic pathways specifically deregulated in ovarian CSCs. METHODS: We developed a new technique based on hyperspectral stimulated Raman scattering imaging of single living cells coupled with electrospray ionization mass spectrometry (ESI-MS) analysis of extracted lipids to identify unique metabolic spectra of ovarian CSCs. SiRNA knockdown and pharmacological inhibitors were used to block fatty acid desaturases and to measure effects on the ovarian CSCs charcateristics. RESULTS: We report significantly increased levels of unsaturated lipids in flow-sorted ovarian CSCs (ALDH+CD133+) compared to non-CSCs (ALDH-CD133-). Higher lipid unsaturation levels were also detected in CSC-enriched spheroids compared to monolayer cultures of ovarian cancer cell lines or primary cells derived from human ovarian tumors. ESI-MS identified that the elevated unsaturation in lipid droplets involved an enhanced conversion from saturated fatty acids (18:0) to unsaturated fatty acids (18:1). Expression of fatty acid desaturases was increased in ovarian CSCs compared to non-CSCs. Pharmacological inhibition or siRNA knockdown of lipid desaturases Δ9 (SCD1) or Δ6 effectively eliminated CSCs, suppressed sphere formation in vitro, and blocked tumor initiation capacity in vivo, as measured by a tumor initiation dilution assay. Mechanistically, the lipid desaturase inhibitors suppressed ovarian cancer cell stemness by blocking the NF-κB survival pathway. Chromatin immunoprecipitation and overexpression of RelA demonstrated that NF-κB transcriptionally regulates SCD1 expression. Collectively, our data suggest that a positive feedback loop involving lipid desaturases, NF-κB, and the stem cell marker ALDH1 can be effectively blocked by SCD1 inhibitors, suppressing ovarian CSCs. CONCLUSIONS: These results demonstrate that increased lipid unsaturation is a novel metabolic marker for ovarian CSCs and a target for CSC-specific therapy. Citation Format: Junjie Li, Salvatore Condello, Jessica Thomes-Pepin, Xiaoxiao Ma, Yu Xia, Thomas D. Hurley, Ji-Xin Cheng, Daniela Matei. LIPID DESATURATION IS A METABOLIC MARKER AND THERAPEUTIC TARGET OF OVARIAN CANCER STEM CELLS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP21.

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Comparative Proteomics Analysis Reveals the Reversal Effect of Cryptotanshinone on Gefitinib-Resistant Cells in Epidermal Growth Factor Receptor-Mutant Lung Cancer

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Identification of a novel lipid metabolism-related gene signature for predicting colorectal cancer survival

“…Numerous evidences from preclinical and clinical data support that the cancer stem cells (CSCs) are responsible for tumor recurrence (Peitzsch et al, 2017;Clarke, 2019). Lipid metabolism has been reported as potential target in bulk and CSCs, including CRC (Li et al, 2017;Choi et al, 2019). A previous study showed that blocking stearoyl-CoA desaturase 1 (SCD1) expression or function inhibited the survival of CSCs, but not bulk colorectal cancer cells in vitro and in vivo (Yu et al, 2021b).…”