Lipid Storage and Autophagy in Melanoma Cancer Cells

Abstract

Cancer stem cells (CSC) represent a key cellular subpopulation controlling biological features such as cancer progression in all cancer types. By using melanospheres established from human melanoma patients, we compared less differentiated melanosphere-derived CSC to differentiating melanosphere-derived cells. Increased lipid uptake was found in melanosphere-derived CSC vs. differentiating melanosphere-derived cells, paralleled by strong expression of lipogenic factors Sterol Regulatory Element-Binding Protein-1 (SREBP-1) and Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ). An inverse relation between lipid-storing phenotype and autophagy was also found, since microtubule-associated protein 1A/1B-Light Chain 3 (LC3) lipidation is reduced in melanosphere-derived CSC. To investigate upstream autophagy regulators, Phospho-AMP activated Protein Kinase (P-AMPK) and Phospho-mammalian Target of Rapamycin (P-mTOR) were analyzed; lower P-AMPK and higher P-mTOR expression in melanosphere-derived CSC were found, thus explaining, at least in part, their lower autophagic activity. In addition, co-localization of LC3-stained autophagosome spots and perilipin-stained lipid droplets was demonstrated mainly in differentiating melanosphere-derived cells, further supporting the role of autophagy in lipid droplets clearance. The present manuscript demonstrates an inverse relationship between lipid-storing phenotype and melanoma stem cells differentiation, providing novel indications involving autophagy in melanoma stem cells biology.

Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells

“…ª 2020 The Authors The EMBO Journal 39: e102525 | 2020 stem cells store lipids mobilized by lipophagy during differentiation of these cells (Giampietri et al, 2017). Transferred FA that fuel FAO may remodel the mitochondrial network in melanoma cells to redistribute these organelles to the cell extremities, which promotes cell migration.…”

Adipocyte vesicles: ‘all-in-one’ packages that stimulate tumor mitochondrial metabolism and dynamics

“…Lipophagy inhibitors prevented the degradation of stored lipids in response to adipocyte EV in both lean and obese conditions. Although the involvement of lipophagy in melanoma metabolism remains unclear, a recent study found that melanospheres containing cancer stem cells store lipids mobilized during differentiation of these cells by lipophagy (Giampietri et al, 2017).…”

Targeting cancer stem cell pathways for cancer therapy

“…387 Furthermore, expression of PPARγ restrains YAP transcriptional activity to induce differentiation in osteosarcoma stem cells 388 and melanoma cells. 389 The PPARγ/NF-κB pathway promotes M2 polarization of macrophages to prevent cell death in ovarian CSCs 4.390 PPARγ activation promotes expression of its target gene PTEN to inhibit PI3K/Akt/ mTOR signaling, which stunts self-renewal, tumorigenicity, and metastasis in cervical CSCs, glioblastoma stem cells, and liver CSCs. 391,392 However, combined expression of Dnmt3a and Dnmt3b inhibits PPARγ expression by direct methylation of its promoter in squamous carcinomas.…”