Surgery-Induced Neutrophil Extracellular Traps Promote Tumor Metastasis by Reprogramming Cancer Cell Lipid Metabolism

Area of Science:

• Oncology
• Immunology
• Metabolic Research

Background:

• Cancer surgery can paradoxically promote tumor recurrence and metastasis through inflammatory responses.
• Neutrophil extracellular traps (NETs) are implicated in cancer progression, but their role in surgery-induced effects is unclear.

Purpose of the Study:

• To investigate how surgery-induced NETs reprogram cancer cell metabolism to promote metastatic growth.
• To explore the potential of targeting NET formation and fatty acid oxidation for preventing postsurgical tumor progression.

Main Methods:

• Mice with tumors underwent surgical procedures to model surgery's effects.
• NET formation was inhibited using DNAse, GSK484, or genetic knockout.
• Cancer cells were analyzed for MYC pathway activation, fatty acid uptake, and oxidation (FAO).
• FAO was blocked using etomoxir, and patient data were analyzed.

Main Results:

• Surgery accelerated primary tumor growth and lung metastasis in mice.
• Inhibiting NET formation or FAO significantly reduced postsurgical tumor growth.
• Cancer cells exposed to surgery or NETs showed increased MYC activation and FAO, including CD36 upregulation.
• Blocking FAO prevented NET-mediated metastatic growth and supported circulating tumor cell survival.

Conclusions:

• Surgery-induced NETs promote tumor progression by activating the MYC pathway and reprogramming cancer cell metabolism towards fatty acid oxidation.
• Targeting the interplay between inflammation (NETs) and metabolism (FAO) presents a promising strategy to prevent postsurgical cancer metastasis.