Lipid droplets are a metabolic vulnerability in melanoma

Abstract

Melanoma exhibits numerous transcriptional cell states including neural crest-like cells as well as pigmented melanocytic cells. How these different cell states relate to distinct tumorigenic phenotypes remains unclear. Here, we use a zebrafish melanoma model to identify a transcriptional program linking the melanocytic cell state to a dependence on lipid droplets, the specialized organelle responsible for lipid storage. Single-cell RNA-sequencing of these tumors show a concordance between genes regulating pigmentation and those involved in lipid and oxidative metabolism. This state is conserved across human melanoma cell lines and patient tumors. This melanocytic state demonstrates increased fatty acid uptake, an increased number of lipid droplets, and dependence upon fatty acid oxidative metabolism. Genetic and pharmacologic suppression of lipid droplet production is sufficient to disrupt cell cycle progression and slow melanoma growth in vivo. Because the melanocytic cell state is linked to poor outcomes in patients, these data indicate a metabolic vulnerability in melanoma that depends on the lipid droplet organelle.

The lipid droplet protein DHRS3 is a regulator of melanoma cell state

“…14,52–55 These fatty acids can be used for diverse processes including incorporation into membranes, β-oxidation, or conversion into acetyl-CoA and subsequent protein acetylation. 12,15,56–60 Lipids can also play a key role in ferroptosis, a central mediator of cancer cell survival. Dependent on fatty acid saturation, excess lipids can promote ferroptosis through lipid peroxidation while uptake of monounsaturated fatty acids can protect cancer cells from ferroptosis.…”

“…For example, a recently developed proximity labeling approach in U2OS osteosarcoma and Huh7 hepatocellular carcinoma cells generated a high confidence list of LD proteins 20 revealing both expected but also unexpected components of the membrane. At a functional level, genetic perturbation of lipid droplet proteins such as DGAT1 12,13,76,77 or PLIN2 78–80 can affect many canonical hallmarks of cancer such as proliferation, invasion, metastasis and drug resistance.…”

“…However, there is increasing interest in understanding the complex role of lipid droplets in cellular metabolism across a diversity of cell types and disease states. Recent research has clearly demonstrated the importance of lipid droplet formation and function in melanoma, 12–14 however we do not fully understand how lipid droplet formation affects disease progression. Furthermore, the dynamic regulation of the lipid droplet in this lineage remains an open area of investigation.…”

“…15 Conversely, melanocytic melanoma cells, which are more oxidative, rely on increased lipid droplet content to support unsaturated fatty acid flux through the mitochondria. 12 These observations imply that the regulation and function of lipid droplets is highly dependent on cellular context and substrate availability. Furthermore, they suggest that lipid droplets may be linked to distinct transcriptional cell states.…”

Phospholipid isotope tracing reveals β-catenin-driven suppression of phosphatidylcholine metabolism in hepatocellular carcinoma

“…Zebrafish ( Danio rerio ) are a vertebrate model organism with a complete immune system and metabolic network that show high conservation with mammals and have been used to study multiple aspects of tumor biology. The use of zebrafish tumor models has recently expanded to include the study of tumor metabolism and several groups have successfully exploited zebrafish to study the metabolism of melanoma (Lumaquin-Yin et al, 2023; Naser et al, 2021). We previously reported a zebrafish model of HCC driven solely by a CTNNB1 transgene that recapitulates human HCC morphologically and transcriptionally in as little as 10 weeks (Evason et al, 2015).…”