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- W4280494679 abstract "Robust neutrophil (PMN) tissue accumulation is an important clinical feature in active Ulcerative Colitis (UC) lesions and in colorectal cancer (CRC). Using murine colitis-associated CRC model, we observed prominent and persistent PMN accumulation as the inflamed colon tissue progressed from colonic ulceration to CRC. Given the emerging evidence of PMN phenotypic and functional heterogeneity in homeostatic and pathologic conditions, we analyzed the transcriptomic landscape of these immune cells in blood and tissue during the transition from inflammatory ulceration to CRC. Principal component analysis effectively stratified neutrophils across different conditions into three discrete clusters that marked distinct spatial compartments of peripheral blood, inflamed colon tissue and the CRC tumor niche. Importantly, combinatory analyses of pathway overrepresentation, protein-network mapping, and gene-ontology scoring revealed a robust enrichment of biological pathways involved in vasculature development and angiogenesis uniquely in PMNs associated with the advanced CRC niche. These findings were validated in vivo as we found that temporary PMN depletion profoundly reduced tumor vascularity, vessel branching, and penetration depth of the tumor vessels. Moreover, we identified Spp1 (OPN) and Mmp14(MT1-MMP) to be highly induced transcriptionally in PMNs as they left the circulation and entered the tumor niche, where Spp1 and Mmp14 directly promoted tumor angiogenesis. TCGA data mining and validation in UC/CRC patient cohorts further confirmed significant upregulation of Spp1 and Mmp14in high-grade CRC, but not in UC patients. In conclusion, the current study identified a niche-specific compartmentalization of PMN transcriptional programing, highlighting the novel PMN plasticity. Our findings further established the contribution of CRC-associated PMNs via Spp1/Mmp14 activity to the formation of a complex tumor vasculature and subsequent neoplastic progression from inflammatory colitis to advanced CRC." @default.
- W4280494679 created "2022-05-22" @default.
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- W4280494679 date "2022-05-01" @default.
- W4280494679 modified "2023-09-24" @default.
- W4280494679 title "Niche‐specific transcriptional reprogramming leads to pro‐angiogenic neutrophil specialization in colon cancer" @default.
- W4280494679 doi "https://doi.org/10.1096/fasebj.2022.36.s1.0r767" @default.
- W4280494679 hasPublicationYear "2022" @default.
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