Gastroenterology

Gastroenterology

Volume 161, Issue 1, July 2021, Pages 225-238.e15
Gastroenterology

Original Research
Full Report: Basic and Translational—Alimentary Tract
Neutrophils Alter DNA Repair Landscape to Impact Survival and Shape Distinct Therapeutic Phenotypes of Colorectal Cancer

https://doi.org/10.1053/j.gastro.2021.03.027Get rights and content

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.

Section snippets

Human Samples

For expression analyses, freshly frozen resected human CRC tissue was obtained from the Northwestern University-Robert H. Lurie Comprehensive Cancer Center Pathology Core Facility with approval by and in accordance with Northwestern University institutional review board protocol. For histological analyses of genomic instability (GI) features, colon cancer tissue arrays CO992a (43 cases/99 cores) and CO962 (48 cases/96 cores) were used (US Biomax Inc, Rockville, MD). For immunofluorescence

Tumor-Infiltrating PMNs Exert Functional Dualism to Temporally Suppress or Promote Tumor Development

PMNs cause genotoxicity in colon epithelium by promoting DSB accumulation, leading to GI.6,8 Because GI is a hallmark of cancer,9 we performed correlative and quantitative analyses of PMN frequency and abundance of key GI markers, micronuclei (MNs), and lagging chromosomes,10 in sporadic CRC. Phenotypic scoring of 70 CRC biopsies (Bio-Matrix tissue microarray) from grades 1 to 3 revealed that formation of MNs and lagging chromosomes was mutually correlated across CRC tissues, and that both GI

Discussion

Distinct PMN populations can mediate anti- and pro-tumorigenic activities1,2; however, we demonstrate for the first time that the anti- or pro-tumorigenic outcomes may respectively arise from the immediate cytotoxic impact of PMNs and the PMN-driven long-term cellular reprogramming in cancer cells. Our findings reconcile seemingly opposing roles of PMNs in cancer and support the idea of potential temporal differences in PMN responses in tumorigenesis. Indeed, PMN presence in low-grade CRC has

Acknowledgments

The authors thank the Northwestern University Center for Advanced Microscopy core (supported by National Cancer Institute CCSG P30 CA060553 awarded to the Lurie Comprehensive Cancer Center) for helping with the imaging experiments, and Lurie Cancer Center Pathology Core Facility for helping with obtaining and processing of CRC tissue.

CRediT Authorship Contributions

Triet M. Bui, BS (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Funding acquisition: Lead; Investigation: Lead; Methodology: Lead; Writing –

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    Conflict of interest The authors disclose no conflicts.

    Funding This work was supported by grants from the Digestive Health Foundation, American Cancer Society Research Scholar Award, and Crohn’s & Colitis Foundation Senior Research Award to Ronen Sumagin, and the Department of Defense’s Congressionally Directed Medical Research Program Horizon Award to Triet M. Bui. Lisa Wiesmüller was supported by the German Research Foundation (DFG) Grant Project B3 in Research Training Group GRK 2254 “Heterogeneity and evolution in solid tumors (HEIST).”

    Author names in bold designate shared co-first authorship.

    Authors contributed equally.

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