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

Abstract Cancer surgery is a double-edged sword, as it can induce an inflammatory response that promotes tumor recurrence and progression. In this study, we explored the effects of surgery-induced neutrophil extracellular traps (NET) in reprogramming cancer metabolism to foster metastatic tumor growth. To model the effect of surgery on tumor progression, mice bearing subcutaneous tumors underwent a midline laparotomy with mesenteric exploration for 30 minutes. Mice subjected to surgery showed accelerated primary subcutaneous and lung metastatic tumor growth. Perioperative inhibition of NET formation utilizing DNAse, GSK484, or peptidyl arginine deiminase 4 knockout mice prevented surgically induced tumor growth, whereas pretreating cancer cells with NETs in vitro before inoculation increased tumor burden. Cancer cells exposed to surgical stress in vivo or treated with NETs in vitro showed activation of the MYC oncogenic pathway and fatty acid (FA) oxidation (FAO). NETs also stimulated the uptake of long-chain FAs and upregulation of CD36, the main long-chain FA transporter. Blocking FAO with etomoxir, a carnitine palmitoyl transferase Iα inhibitor, prevented metastatic tumor growth induced by surgical NETs. FA metabolism was crucial for cancer cells under anoikis stress, allowing the survival of circulating cancer cells exposed to NETs. Analysis of patient data substantiated the correlation between NET abundance and lipid metabolism, and plasma from postoperative patients upregulated CD36 expression and promoted the proliferation of colorectal cancer cells. Together, these findings show that the systemic NETosis response triggered by surgery promotes tumor progression by activating the MYC transcriptional program and reprogramming FAO metabolism in cancer cells. Significance: Surgery stimulates formation of neutrophil extracellular traps that promote fatty acid oxidation to support survival of disseminated cancer cells and metastasis, indicating that targeting this inflammation-metabolism axis may prevent tumor progression.