Tissue-specific reprogramming leads to angiogenic neutrophil specialization and tumor vascularization in colorectal cancer
Triet M. Bui, … , Stephen B. Hanauer, Ronen Sumagin
Triet M. Bui, … , Stephen B. Hanauer, Ronen Sumagin
Published February 8, 2024
Citation Information: J Clin Invest. 2024;134(7):e174545. https://doi.org/10.1172/JCI174545.
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Research Article Gastroenterology Immunology

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

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.

Authors

Triet M. Bui, Lenore K. Yalom, Edward Ning, Jessica M. Urbanczyk, Xingsheng Ren, Caroline J. Herrnreiter, Jackson A. Disario, Brian Wray, Matthew J. Schipma, Yuri S. Velichko, David P. Sullivan, Kouki Abe, Shannon M. Lauberth, Guang-Yu Yang, Parambir S. Dulai, Stephen B. Hanauer, Ronen Sumagin

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Figure 5

TANs modulate multimodal parameters of vascular architecture and spatial organization.

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TANs modulate multimodal parameters of vascular architecture and spatial...
(A) Representative confocal microscopy images of whole-mount tumor vasculature (stained for PECAM-1) in early and advanced PMNhi versus PMNlo tumors. Scale bar: 50μm. Images are representative of n = 6 tumors with 50–70 FOVs per condition. (B) Illustration of 8 architectural parameters assessed for vascular architecture within tumors and tumor-adjacent regions. (C–J) Quantification of architectural and spatial organization factors constructing the vasculature observed in PMNhi versus PMNlo tumors and the nontumor submucosal capillary plexus. For panels C–H, each data point represents an individual FOV (600–1,000 vessels analyzed from 50–70 FOVs from 6–8 mice/condition) shown as distribution of the indicated parameters with median values (black line) and 25th to 75th quartiles (white line). For panels I and J, each data point represents a tumor-bearing mouse with combined FOV analysis from all tumors. *P < 0.05, ***P < 0.001, ****P < 0.0001, 1-way ANOVA with Tukey’s multiple comparison test.