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Original Research Full Report: Basic and Translational—Alimentary Tract| Volume 161, ISSUE 1, P225-238.e15, July 01, 2021

Neutrophils Alter DNA Repair Landscape to Impact Survival and Shape Distinct Therapeutic Phenotypes of Colorectal Cancer

      Background & aims

      Tumor-infiltrating neutrophils (polymorphonuclear neutrophils [PMNs]) are a prominent feature of colorectal cancer (CRC), where they can promote cytotoxicity or exacerbate disease outcomes. We recently showed that in acute colon injury, PMNs can increase DNA double-strand break (DSB) burden and promote genomic instability via microRNA-dependent inhibition of homologous recombination (HR) repair. In this study, we aimed to establish whether in inflamed colon, neutrophils shape the DSB-repair responses to impact CRC progression and sensitivity/resistance to DNA-repair targeted therapy.

      Methods

      Human sporadic CRC biopsies, The Cancer Genome Atlas gene expression analyses, tumor xenografts, and murine CRC models, as well as small-molecule inhibition of key DSB-repair factors were leveraged to investigate changes in the DSB-repair landscape and identify unique CRC responses with/without tumor infiltration by PMNs.

      Results

      We reveal that neutrophils exert a functional dualism in cancer cells, driving temporal modulation of the DNA damage landscape and resolution of DSBs. PMNs were found to promote HR deficiency in low-grade CRC by miR-155-dependent downregulation of RAD51, thus attenuating tumor growth. However, neutrophil-mediated genotoxicity due to accumulation of DSBs led to the induction of non-homologous end-joining (NHEJ), allowing for survival and growth of advanced CRC. Our findings identified a PMN-induced HR-deficient CRC phenotype, featuring low RAD51 and low Ku70 levels, rendering it susceptible to synthetic lethality induced by clinically approved PARP1 inhibitor Olaparib. We further identified a distinct PMN-induced HR-deficient CRC phenotype, featuring high Ku70 and heightened NHEJ, which can be therapeutically targeted by specific inhibition of NHEJ.

      Conclusions

      Our work delineates 2 mechanism-based translatable therapeutic interventions in sporadic CRC.

      Graphical abstract

      Keywords

      Abbreviations used in this paper:

      AOM (Azoxymethane), CDKN (Cyclin-dependent Kinase Inhibitor), CMPT (Camptothecin), CRC (colorectal cancer), DSBs (double-strand breaks), DSS (Dextran Sodium Sulfate), EGFP (Enhanced Green Fluorescence Protein), GI (Genomic Instability), HR (homologous recombination), MN (Micronuclei), NHEJ (non-homologous end-joining), PMNs (polymorphonuclear neutrophils), TUNEL (TdT-mediated dUTP nick end-labeling), WT (wild type), γH2AX (phospho-S139 Histone 2AX variant), 53BP1 (p53 Binding Protein 1)
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