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 10

MMP14 inhibition curbs tumor growth in a CRC PDX model.

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MMP14 inhibition curbs tumor growth in a CRC PDX model. (A) Schematic of...
(A) Schematic of human CRC tumor grafting into NGS mice, followed by vehicle control (C) or MMP14i treatment (M, NSC405020, 2.0 mg/kg/day (45)). (B) Spaghetti plots of individual PDX tumor growth curves and (C) Representative endpoint PDX images (day 42/week 6). Scale bar: 1cm. (D) Quantification of endpoint tumor burden indexed by volume and (E) weight following MMP14 inhibition (vehicle, n = 4; MMP14i, n = 6 mice). (F) Representative whole-mount, fluorescence confocal microscopy images of endpoint PDX vasculature (stained for PECAM-1). Scale bar: 50μm. (G–I) Quantification of vascular architecture parameters from endpoint tumor vessel images. Images are representative of n = 4–6 mice per condition with 50–75 FOVs analyzed per group. For I, a total of approximately 1000 vessels per treatment were analyzed. **P < 0.01, ****P < 0.0001, 2-sided student’s t test.