Abstract
Neutrophil (PMN) tissue accumulation is an established feature of ulcerative colitis (UC) lesions and colorectal cancer (CRC). To assess the PMN phenotypic and functional diversification during the transition from inflammatory ulceration to CRC we analyzed the transcriptomic landscape of blood and tissue PMNs. Transcriptional programs effectively separated PMNs based on their proximity to peripheral blood, inflamed colon, and tumors. 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 mechanistic studies to be highly induced in TANs, acting to critically regulate endothelial cell chemotaxis and branching. TCGA data set and clinical specimens confirmed enrichment of SPP1 and MMP14 in high-grade CRC but not in patients with UC. Pharmacological inhibition of TAN trafficking or MMP14 activity effectively reduced tumor vascular density, leading to CRC regression. Our findings demonstrate a niche-directed PMN functional specialization and identify TAN contributions to tumor vascularization, delineating what we believe to be a new therapeutic framework for CRC treatment focused on TAN angiogenic properties.
Original language | English (US) |
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Article number | e174545 |
Journal | Journal of Clinical Investigation |
Volume | 134 |
Issue number | 7 |
DOIs | |
State | Published - Apr 1 2024 |
Funding
This work was supported by the Northwestern University, NUSeq core facility funded by NIH Grant 1S10OD025120 for housing the 10x Chromium. The non-clinical research histopathology and molecular phenotyping services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory (MHPL), which is supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. This work was supported by grants from the Digestive Health Foundation, American Cancer Society Research Scholar Award Crohn’s & Colitis Foundation Senior Research Award, and NIH NIDDK/NIAID R01s, DK124199 and AI153568 and the Department of Defense’s Congressionally Directed Medical Research Program Horizon Award to TMB.
ASJC Scopus subject areas
- General Medicine