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

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Neutrophil (PMN) accumulation is characteristic of ulcerative colitis (UC) and colorectal cancer (CRC).
• Understanding PMN functional changes during the progression from inflammation to cancer is crucial.

Purpose of the Study:

• To investigate the phenotypic and functional diversification of PMNs during the transition from inflammatory ulceration to CRC.
• To identify specific pathways and molecules involved in PMN function in the tumor microenvironment.

Main Methods:

• Transcriptomic analysis of blood and tissue PMNs from patients and murine models.
• In silico pathway analysis, protein-network mapping, and gene-ontology scoring.
• Ex vivo functional studies, including murine CRC and patient-derived xenograft models.
• Analysis of TCGA dataset and clinical specimens.

Main Results:

• Transcriptional analysis separated PMNs based on location (blood, inflamed colon, tumor).
• Tumor-associated neutrophils (TANs) showed enrichment in angiogenic and vasculature development pathways.
• TANs, particularly via Spp1 (OPN) and Mmp14 (MT1-MMP), critically promoted tumor vascularization and endothelial cell function.
• Pharmacological inhibition of TAN trafficking or MMP14 reduced tumor vascular density and led to CRC regression.

Conclusions:

• PMNs undergo niche-directed functional specialization, with TANs playing a key role in tumor vascularization.
• SPP1 and MMP14 are identified as critical regulators of TAN function in CRC.
• Targeting TAN angiogenic properties presents a potential therapeutic strategy for colorectal cancer.