01
ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization
Wang Y. et al.
Cell. 2024
The researchers found that metastatic ovarian cancer cells, compared to non-metastatic ones, exhibit higher levels of polyunsaturated lipids. These lipids serve as substrates for lipid peroxidation, which, in the presence of iron, promotes ferroptosis sensitivity. This suggests that lipid composition directly influences metastatic potential. Using a multi-stage screening process, the study identified key metabolic genes, including NMNAT1, which are critical for metastasis to organs like the liver and lungs. These genes help ovarian cancer cells colonize distant organs.
The study's central finding is the role of ACSL4, an enzyme involved in the metabolism of polyunsaturated fatty acids. ACSL4 converts unsaturated fatty acids into acyl-CoA, supporting phospholipid synthesis and fatty acid oxidation. This process is essential for maintaining cell membrane fluidity and energy supply. ACSL4 was found to be crucial for the extravasation of cancer cells from blood vessels, facilitating lung and liver metastasis.
Interestingly, while ACSL4 deletion inhibited the extravasation step, it did not eliminate metastasis, indicating that ACSL4 is more critical in early metastasis stages. This suggests that targeting ACSL4 could inhibit early metastasis, but additional strategies would be needed to address later stages of colonization.
The study also examined the role of fatty acid β-oxidation in metastatic cells. Cells with high unsaturated lipid content rely on enzymes like ECI1 and ECH1 for processing these lipids. Inhibiting ECI1 and ECH1 disrupted metastatic growth, offering a potential therapeutic strategy.
Overall, the research highlights ACSL4 and polyunsaturated lipid metabolism as key targets in ovarian cancer metastasis. Targeting these pathways could offer novel therapeutic approaches to inhibit tumor spread, with potential implications for other cancers as well.
DOI: 10.1016/j.cell.2024.10.047
02
Arseniy E. et al.
Nat Cell Biol. 2024
The research shows that astrocytes, through secretion of factors like emilin-1, induce excessive expression of CDK5 in BrM cells, which promotes tumor growth in mouse models. CDK5 expression is significantly higher in BrM compared to primary breast tumors and correlates with poor survival in patients. Knockdown of CDK5 (CDK5-KD) in BrM cells extended survival in mice, highlighting its critical role in BrM progression.
The study further reveals that CDK5 suppresses MHC-I expression, aiding immune evasion. CDK5-KD led to a significant upregulation of MHC-I at both mRNA and protein levels, enhancing antigen presentation. In functional assays, CDK5 knockdown increased CD8+ T-cell-mediated cytotoxicity against tumor cells. CDK5 inhibits MHC-I expression via the Stat1-importinα-Nlrc5 signaling pathway. CDK5-induced phosphorylation of Irf2bp1 at S66 suppressed Stat1 and Nlrc5 activation, reducing MHC-I presentation on tumor cells and promoting immune escape.
Therapeutic targeting of CDK5 was also explored, showing that treatment with RSV, a CDK5 inhibitor, restored MHC-I expression and enhanced the immune response. RSV treatment reduced BrM growth and increased CD8+ T-cell infiltration in tumors. Combination therapy with RSV and PD-1 inhibitors further suppressed BrM burden, demonstrating that CDK5 inhibition enhances the efficacy of immune checkpoint inhibitors.
In conclusion, the study identifies CDK5 as a key regulator of immune evasion in BrM by downregulating MHC-I expression. Targeting CDK5 not only restores immune recognition but also enhances the effectiveness of immune checkpoint therapies, providing a promising strategy to treat brain metastases in breast cancer.
DOI: 10.1038/s41556-024-01509-5
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