Lipid droplets are a metabolic vulnerability in melanoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA831276 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18901600_1.fastq.gz | Fastqsanger.gz | |||
| SRR18901600_2.fastq.gz | Fastqsanger.gz | |||
| SRR18901601_1.fastq.gz | Fastqsanger.gz | |||
| SRR18901601_2.fastq.gz | Fastqsanger.gz | |||
| SRR18901602_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
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Project description:Lipid droplets (LDs) store lipids for metabolic energy and are central to cellular lipid homeostasis. The mechanisms coordinating lipid storage in LDs with cellular metabolism are unclear but relevant to obesity-related diseases. Here we utilized genome-wide screening to identify genes that modulate lipid storage in human macrophages, a cell type relevant to metabolic diseases. Among ~550 genes regulating lipid storage, we identify MLX, a basic helix-loop-helix leucine-zipper transcription factor that regulates multiple metabolic processes. We show that MLX and family members MLXIP/MondoA and MLXIPL/ChREBP bind LDs via C-terminal amphipathic helices. When LDs increase in cells, LD binding of MLX, MLXIP/MondoA, and MLXIPL/ChREBP reduces their transcriptional activity, whereas the absence of LDs results in hyperactivation. Our findings uncover an unexpected component to a lipid storage response, in which binding of MLX transcription factors to the LD surface modulates their activity, adjusting the expression of metabolic genes to lipid storage levels.
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Project description: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.
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Project description:Lipid droplets are fat storage organelles composed of a protein envelope and a lipid rich core. Dynamic regulation of this protein envelope underlies differential lipid droplet formation and function in diverse cell types. In melanoma, the ability to form lipid droplets has been linked to tumor progression and metastasis, but it is not known whether lipid droplet proteins play a role in these phenotypes. To address this, we performed proteomic analysis of the lipid droplet envelope in melanoma. We found that proteins expressed in the lipid droplet were differentially enriched in distinct melanoma states, ranging from melanocytic to neural crest like. DHRS3, which is involved in the conversion of all-trans-retinal to all-trans-retinol, is significantly upregulated in the MITFLO/neural crest-like melanoma cell state, and markedly reduced in the MITFHI/melanocytic state. Increased DHRS3 expression is sufficient to drive the MITFHI/melanocytic cells to a more undifferentiated and invasive state. These changes are due to retinoic acid mediated regulation of melanocytic genes through the retinoid X receptors (RXR). Our data demonstrate that melanoma cell state can be regulated by expression of lipid droplet proteins which affect downstream retinoid signaling.
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