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• W3176175931 abstract "Exacerbated Inflammation that can be driven by neutrophil (PMN) infiltration is one of the major risk factors for development and progression of colorectal cancer (CRC). Using a biopsy-based acute-injury model, we previously showed that miRNAs derived from PMN-microparticles (MPs) inhibit Homologous Recombination (HR), leading to accumulation of Double-Strand Breaks (DSBs). These observations led us to investigate the effects of long-term exposure of intestinal epithelial cancer cells HCT116 to PMNs and PMN-MPs. Consistent with the acute-injury model, long-term PMN-MP treatment led to HR suppression with concomitant accumulation of DSBs, increased aneuploidy and apoptosis within 7 population doublings (PD7). With continued HR inhibition by PMN-MPs, by PD12 we observed an upregulation of Non-Homologous End-Joining (NHEJ) activity. Importantly, DSBs and cell apoptosis were also significantly decreased at PD12, despite elevated aneuploidy, suggesting that PMN-induced NHEJ activation promotes tumor cell survival and aneuploidy. To test this in vivo, we employed a tumor xenograft model in conjunction with an antibody-based PMN depletion strategy. Consistent with in vitro observations, HR inhibition, NHEJ upregulation, decreased apoptosis, and increased aneuploidy were confirmed in PMN-infiltrated (PMN+) tumors as compared to PMN-depleted (PMN−) tumors. To examine whether PMNs indeed provide survival advantage to tumor cells and help them overcome DSB accumulation, we performed ex vivo clonogenicity assay, where cells were challenged with DSB-inducing agents Camptothecin (CMPT). PMN+ tumor cells were resistant to CMPT treatment and were able to more efficiently re-propagate compared to parental HCT116 cells and PMN- tumor cells, which underwent apoptosis in response to CMPT-induced genotoxic stress. Consistently, in PMN- tumor cells, upregulation of H2AX and cell cycle regulatory genes (p16INK4a, p27Kip1, TP53, p21Cip1) was observed, indicating inefficient DNA Damage repair. As such, our findings define a new regulatory role of PMNs in promoting CRC survival during carcinogenesis. Support or Funding Information This work was supported by grants from the National Institutes of Health (NIH) DK101675, Digestive Health Foundation, Chicago and by the Robert H. Lurie Comprehensive Cancer Center (Eisenberg Scholar grant) and by American Cancer Society to Ronen Sumagin. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal." @default.
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• W3176175931 date "2019-04-01" @default.
• W3176175931 modified "2023-09-27" @default.
• W3176175931 title "PMNs promote Non‐Homologous End‐Joining (NHEJ)‐mediated survival of colorectal cancer cells in inflammatory setting" @default.
• W3176175931 doi "https://doi.org/10.1096/fasebj.2019.33.1_supplement.368.11" @default.
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