Triet M Bui1, Veronika Butin-Israeli2, Hannah L Wiesolek1, Meredith Zhou1, Jake F Rehring1, Lisa Wiesmüller3, Jennifer D Wu2, Guang-Yu Yang1, Stephen B Hanauer4, Julien A Sebag5, Ronen Sumagin6. 1. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 2. Department of Urology and Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 3. Department of Obstetrics and Gynecology, Ulm University, Germany. 4. Department of Medicine, Gastroenterology and Hepatology Northwestern Memorial Hospital, Chicago, Illinois. 5. Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa. 6. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address: ronen.sumagin@northwestern.edu.
Abstract
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.
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.
Authors: Ayush Batra; Triet M Bui; Jacob F Rehring; Lenore K Yalom; William A Muller; David P Sullivan; Ronen Sumagin Journal: Am J Pathol Date: 2021-11-10 Impact factor: 4.307
Authors: Antonio Martínez-Gutierrez; Berenice Carbajal-Lopez; Triet M Bui; Monica Mendoza-Rodriguez; Alma D Campos-Parra; Germán Calderillo-Ruiz; David Cantú-De Leon; Eduardo-Osiris Madrigal-Santillán; Ronen Sumagin; Carlos Pérez-Plasencia; Eloy-Andrés Pérez-Yépez Journal: Biochem Biophys Rep Date: 2022-03-18