Aberrant lipid metabolism as an emerging therapeutic strategy to target cancer stem cells

Abstract

Emerging evidence in cancer metabolomics has identified reprogrammed metabolic pathways to be a major hallmark of cancer, among which deregulated lipid metabolism is a prominent field receiving increasing attention. Cancer stem cells (CSCs) comprise <0.1% of the tumor bulk and possess high self-renewal, tumor-initiating properties, and are responsible for therapeutic resistance, disease recurrence, and tumor metastasis. Hence, it is imperative to understand the metabolic rewiring occurring in CSCs, especially their lipid metabolism, on which there have been recent reports. CSCs rely highly upon lipid metabolism for maintaining their stemness properties and fulfilling their biomass and energy demands, ultimately leading to cancer growth and invasion. Hence, in this review we will shed light on the aberrant lipid metabolism that CSCs exploit to boost their survival, which comprises upregulation in de novo lipogenesis, lipid droplet synthesis, lipid desaturation, and β-oxidation. Furthermore, the metabolic regulators involved in the process, such as key lipogenic enzymes, are also highlighted. Finally, we also summarize the therapeutic strategies targeting the key regulators involved in CSCs' lipid metabolism, which thereby demonstrates the potential to develop powerful and novel therapeutics against the CSC lipid metabolome.

Familial autosomal recessive bestrophinopathy: identification of a novel variant in BEST1 gene and the specific metabolomic profile

“…Therefore, the metabolites are closely linked with genetics and also related to the phenotype [10]. Because of the rapid development in biological techniques and bioinformatics, the metabolome has been used to not only identify biomarkers for diagnosis but also provide a therapeutic strategy in diseases [11,12]. In retinal health and disease, some groups have performed metabolomics for disease diagnosis and potential target intervention [10].…”

Dual-mTOR Inhibitor Rapalink-1 Reduces Prostate Cancer Patient-Derived Xenograft Growth and Alters Tumor Heterogeneity

“…Compared to breast cancer, PCa bone metastasis were also enriched for pathways involved in oxidative phosphorylation and lipid metabolism (fatty acid metabolism, peroxisome, adipogenesis, cholesterol homeostasis), a finding in line with an increase in lipid metabolism in more advanced PCa stages (46) and supporting the clinical relevance of targeting this metabolic branch to prevent the development of androgen-resistance (47). An altered lipid metabolism has been linked to CSC for multiple cancer types (48). Given the substrate preferences of the different ALDH isoforms (49), it would be interesting to determine if upregulation of the mTOR pathway induced metabolic rewiring in PCa cells, or metabolic diversification of subpopulations within the tumor.…”

Impact of the Monocarboxylate Transporter-1 (MCT1)-Mediated Cellular Import of Lactate on Stemness Properties of Human Pancreatic Adenocarcinoma Cells

“…Again, few cells remain in the reverse Warburg metabolism and persist in the stem cell-like state favored by lactate utilization [53]. The role of lactate in inducing CRC characteristics under glucose restriction could relate also to an altered lipid metabolism that was recently linked with cancer stemness, too [54]. Thus, the lactate uptake may act in concert with changes in the rate of fatty acid synthesis and transport when glucose supply is low.…”