Journal article
Neutrophils Alter DNA Repair Landscape to Impact Survival and Shape Distinct Therapeutic Phenotypes of Colorectal Cancer
Gastroenterology (New York, N.Y. 1943), Vol.161(1), pp.225-238.e15
03/19/2021
DOI: 10.1053/j.gastro.2021.03.027
PMID: 33753103
Abstract
Tumor-infiltrating 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 breaks (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.
Human sporadic CRC biopsies, TCGA 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.
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.
Our work delineates two mechanism-based translatable therapeutic interventions in sporadic CRC.
Details
- Title: Subtitle
- Neutrophils Alter DNA Repair Landscape to Impact Survival and Shape Distinct Therapeutic Phenotypes of Colorectal Cancer
- Creators
- Triet M Bui - Department of Pathology, Northwestern University Feinberg School of Medicine, 300 East Superior St. Chicago, IL 60611Veronika Butin-Israeli - Department of Urology and Microbiology-Immunology, Northwestern University Feinberg School of Medicine, 300 East Superior St. Chicago, IL 60611Hannah L Wiesolek - Department of Pathology, Northwestern University Feinberg School of Medicine, 300 East Superior St. Chicago, IL 60611Meredith Zhou - Department of Pathology, Northwestern University Feinberg School of Medicine, 300 East Superior St. Chicago, IL 60611Jake F Rehring - Department of Pathology, Northwestern University Feinberg School of Medicine, 300 East Superior St. Chicago, IL 60611Lisa Wiesmüller - Department of Obstetrics and Gynecology, Ulm University, GermanyJennifer D Wu - Department of Urology and Microbiology-Immunology, Northwestern University Feinberg School of Medicine, 300 East Superior St. Chicago, IL 60611Guang-Yu Yang - Department of Pathology, Northwestern University Feinberg School of Medicine, 300 East Superior St. Chicago, IL 60611Stephen B Hanauer - Department of Medicine, Gastroenterology and Hepatology Northwestern Memorial Hospital, 676 N Saint Clair, Chicago IL 60611Julien A Sebag - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242Ronen Sumagin - Department of Pathology, Northwestern University Feinberg School of Medicine, 300 East Superior St. Chicago, IL 60611
- Resource Type
- Journal article
- Publication Details
- Gastroenterology (New York, N.Y. 1943), Vol.161(1), pp.225-238.e15
- Publisher
- Elsevier Inc
- DOI
- 10.1053/j.gastro.2021.03.027
- PMID
- 33753103
- ISSN
- 0016-5085
- eISSN
- 1528-0012
- Grant note
- DOI: 10.13039/100011684, name: Crohn's and Colitis Foundation of America; DOI: 10.13039/100000048, name: American Cancer Society
- Language
- English
- Date published
- 03/19/2021
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984071951102771
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