Neutrophil Extracellular Trap Reprograms Cancer Metabolism to Form a Metastatic Niche Promoting Non-Small Cell Lung...

Area of Science:

• Oncology
• Molecular Biology
• Metabolomics

Background:

• Non-small cell lung cancer (NSCLC) frequently causes brain metastases (BMs), leading to poor prognosis.
• Limited efficacy of current treatments for NSCLC BMs necessitates novel therapeutic strategies.

Purpose of the Study:

• To elucidate the molecular mechanisms driving NSCLC brain metastasis.
• To identify novel therapeutic targets for NSCLC BMs.

Main Methods:

• Multi-omics sequencing (spatial transcriptomics, single-cell RNA sequencing, proteomics, metabolomics) on patient samples.
• Investigation of cellular interactions, signaling pathways (NET-KRT10 axis), and metabolic drivers.
• AI-driven prediction and in vitro/in vivo assays to evaluate therapeutic agents.

Main Results:

• LOX+ Malig-5 cells identified as metastasis-initiating cells (MICs) associated with poor prognosis.
• A novel NET-KRT10 signaling axis involving neutrophils and MICs promotes epithelial-mesenchymal transition (EMT) and metastasis.
• Elevated palmitic acid identified as a key metabolic driver in the metastatic niche.
• Fatty acid synthase inhibitor TVB-2640 demonstrated potential in suppressing NSCLC BMs.

Conclusions:

• NET-dependent interactions and metabolic alterations are crucial in NSCLC brain metastasis.
• TVB-2640 represents a promising therapeutic strategy targeting metabolic vulnerabilities in NSCLC BMs.