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ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization

ABSTRACT: Metastasis is the leading cause of the cancer-related death. To systemically study the dependent factors impacting cancer metastasis, we conducted serial transplantation to obtain ES-2-MC2-Liver cells, a cell line with high metastatic efficiency. We then performed in vivo CRISPR screen using phosphatase and metabolism-focused sgRNA library and ranked differential targeting genes. For further validating the identified gene essentialities in previous results, we generated a mini-library targeting the top-depleted and -enriched genes in metastatic organs and performed in vivo CRISPR screen on ES-2-MC2-Liver cells and SKHEP1 cells. Notably, polyunsaturated lipids synthase, ACSL4, displayed as the top perturbed hits among the lung-specific metastatic mediators. We also evaluated enzymes involved in unsaturated fatty acids degradation were dispensable for metastatic tumor colonization. Taken together, our results systemically study the mediators of cancer metastasis and established the dual functions of PUFA-lipids in tumor progression and metastasis that may be exploitable for therapeutic development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279723 | GEO | 2024/11/25

REPOSITORIES: GEO

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Project description:Withaferin A isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to concentrations of Withaferin A (WA) which can be detected systemically in in vivo experiments. Whereas WA revealed attenuation of multiple cancer hallmarks the withanolide analogue Withanone (WN), did not exert any of the described effects in these cells at comparable concentrations. Pathway enrichment analysis identified that WA targeted relevant cancer programs related to cell death, cell cycle and proliferation, which could functionally be validated flow cytometrically and by real-time proliferation xCELLigence assay. With respect to cell motility, invasion and metastasis processes, WA was found to strongly decrease MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This is further supported by gene expression changes which demonstrate increased expression of a validated breast cancer metastasis suppressor gene (BRMS1) and concomitant decreased expression of extracellular matrix-degrading proteases (PLAU, PLAT, ADAM8), cell adhesion molecules (integrins, laminins) as well as pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R). Subsequent in silico network analysis listed key node transcription factors regulating these processes (p53, E2F1, CDKN2A, NRF2) and revealed the role of chromatin modifying enzymes (p300, JARID1B) as central master switches, linking multiple anticancer activities of WA. Furthermore, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking in account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy resistant triple negative breast cancer, WA based therapeutic strategies hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer. Total RNA from 2 different cell lines treated with WA, are compared to their untreated states

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ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization

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