Pan-Cancer Analysis Reveals a Distinct Neutrophil Extracellular Trap-Associated Regulatory Pattern

Abstract

BackgroundNeutrophils form extracellular net-like structures called neutrophil extracellular traps (NETs). Emerging evidence has shown that cancer can induce NET formation; however, it is not fully understood how NETs influence cancer biology, and no consensus has been reached on their pro- or antitumor effects. A comprehensive analysis of the global NET-associated gene regulatory network is currently unavailable and is urgently needed.MethodsWe systematically explored and discussed NET enrichment, NET-associated gene regulatory patterns, and the prognostic implications of NETs in approximately 8,000 patients across 22 major human cancer types. We identified NET-associated regulatory gene sets that we then screened for NET-associated regulatory patterns that might affect patient survival. We functionally annotated the NET-associated regulatory patterns to compare the biological differences between NET-related survival subgroups.ResultsA gene set variation analysis (GSVA) based on 23 major component genes was used to calculate a metric called the NET score. We found that the NET score was closely associated with many important cancer hallmarks, particularly inflammatory responses and epithelial-to-mesenchymal transition (EMT)-induced metastasis. Higher NET scores were related to poor immunotherapy response. Survival analysis revealed that NETs had diverse prognostic impacts among various cancer types. The NET-associated regulatory patterns linked to shorter or longer cancer patient survival were distinct from each other. Functional analysis revealed that more of the NET-associated regulatory genes linked to poor cancer survival were associated with extracellular matrix (ECM) remodeling and pan-cancerous risk factors. SPP1 was found to be highly expressed and correlated with NET formation in cancers with poor survival. We also found that the co-upregulation of NET formation and SPP1 expression was closely linked to increased EMT and poor survival, that SPP1 influenced NET-induced malignant capacity, and that SPP1 overproduction induced a robust formation of metastatic-promoting NETs.ConclusionNETs were common across cancers but displayed a diverse regulatory pattern and outcome readouts in different cancer types. SPP1 is potentially the key to NET-related poor outcomes.

Cirrhotic-extracellular matrix attenuates aPD-1 treatment response by initiating immunosuppressive neutrophil extracellular traps formation in hepatocellular carcinoma

“…Neutrophils within the TME, which are known to form extracellular traps (NETs), have been shown to exert a complex regulatory capacity in many types of cancer. We have also found that increased neutrophils and NETs promote HCC growth and progression by provoking a tumorous inflammatory response [ 12 , 20 ]. In the present study, the enrichment of NETs was further observed in ECM score-high HCC (Additional file 4 : Fig.…”

Copper metabolism-related risk score identifies hepatocellular carcinoma subtypes and SLC27A5 as a potential regulator of cuproptosis

“…The molecular function analysis of 134 copper related genes was conducted via the ClueGo application in the Cytoscape software [ 34 ]. Gene set variation analysis (GSVA) of the 14 copper metabolism-related pathways in HCC and corresponding normal liver samples was performed by the ‘GSEABase’ and ‘GSVA’ packages in R software [ 35 ]. GSEA of CMscore-based classification of HCC patients was performed as described in our previous works [ 36 ].…”

Shaping the immune‐suppressive microenvironment on tumor‐associated myeloid cells through tumor‐derived exosomes

“…These NETs, intricate network structures resulting from the release of chromatin outside the cell through a specialized death pathway, actively participating in various cellular processes. 31 The role of exosomes in inducing NETs formation has been firmly established across various diseases. 32 Macrophagederived exosomes stimulated by Ox-LDL can promote atherosclerosis by inducing the formation of NETs.…”

“…Moreover, neutrophils can be stimulated by TEXs to form neutrophil extracellular traps (NETs). These NETs, intricate network structures resulting from the release of chromatin outside the cell through a specialized death pathway, actively participating in various cellular processes 31 . The role of exosomes in inducing NETs formation has been firmly established across various diseases 32 .…”