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 (NETs) 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 mins. Mice subjected to surgery showed accelerated primary subcutaneous and lung metastatic tumor growth. Perioperative inhibition of NET formation utilizing DNAse, GSK484, or PAD4 knockout mice prevented surgically induced tumor growth, whereas pre-treating 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 oxidation (FAO). NETs also stimulated uptake of long-chain fatty acids (LCFA) and upregulation of CD36, the main LCFA transporter. Blocking FAO with etomoxir, a CPT1α inhibitor, prevented metastatic tumor growth induced by surgical NETs. FA metabolism was crucial for cancer cells under anoikis stress, allowing survival of circulating cancer cells exposed to NETs. Analysis of patient data substantiated the correlation between NET abundance and lipid metabolism, and plasma from post-operative 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.