Tissue-specific reprogramming leads to angiogenic neutrophil specialization and tumor vascularization in colorectal cancer

ABSTRACT: Polymorphonuclear neutrophil (PMN) tissue accumulation is an established feature of ulcerative colitis (UC) lesions and colorectal cancer (CRC). Given the emerging evidence of PMN phenotypic and functional heterogeneity, we analyzed the transcriptomic landscape of PMNs in blood and tissue during the spatiotemporal transition from inflammatory ulceration to CRC. Based on their transcriptional programs, PMNs were effectively stratified into distinct spatial compartments of peripheral blood, inflamed colon tissue, and the tumor niche. In silico pathway overrepresentation analysis, protein-network mapping, gene signature identification, and gene-ontology scoring revealed unique enrichment of angiogenic and vasculature development pathways in tumor-associated neutrophils (TANs). Functional studies utilizing ex vivo cultures, colitis-induced murine CRC, and patient-derived xenograft models demonstrated a critical role for TANs in promoting tumor vascularization. Spp1 (OPN) and Mmp14 (MT1-MMP) were identified by unbiased -omics and by mechanistic studies to be highly induced in TANs and function to critically regulate endothelial cell chemotaxis and branched network formation. TCGA dataset and clinical specimens confirmed enrichment of SPP1 and MMP14 in high-grade CRC but not in UC patients. Importantly, pharmacological inhibition of TAN trafficking or MMP14 activity effectively reduced tumor vascular density, leading to CRC regression. The current study identified a niche-directed PMN transcriptional reprograming and functional specialization, highlighting emerging PMN plasticity. Our findings define new TAN contributions to tumor vascularization, delineating a new therapeutic framework for CRC treatment focused on TAN angiogenic properties.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE232217 | GEO | 2024/04/01

REPOSITORIES: GEO