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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 Article has an altmetric score of 10

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

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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 11

MMP14 inhibition promotes collagen accumulation and profibrotic programs in CRC PDXs.

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MMP14 inhibition promotes collagen accumulation and profibrotic programs...
(A) Representative fluorescence staining of CRC vasculature (PECAM-1, red) and Collagen I (green, MMP14 substrate) in tumor and stromal regions. Nuclei were counterstained by Hoechst (blue). White outlines and arrows indicate intact and disrupted vessels with abnormal morphologies, respectively. (B) Quantification of fluorescence intensity as an index of Collagen I levels (top) and staining coverage in tumor tissue following the specified treatment (vehicle, n = 4; MMP14i, n = 6 tumors with 50–70 FOVs analyzed per group). ***P < 0.001, ****P < 0.0001, 2-sided student’s t test. (C) Metascape GO analyses of MMP14i-treated tumors highlight enriched pathways involved in Collagen fibril and matrix formation (red, upregulation) versus cell cycle/metabolism (blue, downregulation). A cutoff of FDR < 0.05 following Benjamini-Hochberg’s correction was set for GO enrichment analysis. (D) GSEA of the MSigDB “50 Hallmarks’”gene set specifies pathways upregulated (NES > 0, red) and downregulated (NES < 0, blue) following MMP14i inhibition. Pathways were ranked based on NES with FDR < 0.05 following Benjamini-Hochberg’s correction. (E) Representative H&E (top, scale bar: 500μm) and dual-stained IHC images (middle and bottom, scale bar: 30 μm) of advanced-stage CRC patients enriched for MMP14 and MMP14+ S100A9+ TANs. In H&E view, the cancerous lesions (red outline) and cancer-adjacent colon regions (black outline) of double-core biopsies from a stage III CRC patient were shown. Digital color deconvolution shows separate staining of S100A9 (red), MMP14 (brown), and nuclei (blue) of double-positive TAN clusters (dotted circles) within intratumoral regions.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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