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.
View: Text | PDF
Research Article Gastroenterology Immunology Article has an altmetric score of 10

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

×

Figure 8

Pharmacological inhibition of TAN recruitment or MMP14 inhibition promotes CRC regression.

Options: View larger image (or click on image) Download as PowerPoint
Pharmacological inhibition of TAN recruitment or MMP14 inhibition promot...
(A) Schematic of the treatment regimens. (B) Representative macroscopic images of excised colons and high-resolution endoscopic images of advanced CRC (week 15) treated with either vehicle, anti-VEGFR2 neutralizing mAb (clone DC101(49), 50 mg/kg/day, 3 times/week), CXCR2 inhibitor, Reparixin (5 mg/kg/day (46, 47), daily) or MMP14 allosteric inhibitor NSC 405020 (2.0 mg/kg/day (45), 3 times/week). Scale bar: 1mm. (C) Flow cytometry analyses of Ly6G+/CD11b+/Lyz2hi blood PMN and TAN numbers following indicated treatments (n = 6–9 mice/treatment). (D) Quantifications of tumor penetrance, (E) individual tumor volume, (F) tumor burden (cumulative tumor volume), and (G) cell death indicated by % Annexin V+ and SYTOX-Red+ following flow cytometry analysis (Vehicle/ isotype, n = 9; Anti-VEGFR2, n = 6; Reparixin, n = 6; MMP14, n = 9 mice; 1-way ANOVA with Dunnett’s multiple comparison test). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, 1-way ANOVA with Tukey’s multiple comparison test.