Bui Triet M, Butin-Israeli Veronika, Wiesolek Hannah L, Zhou Meredith, Rehring Jake F, Wiesmüller Lisa, Wu Jennifer D, Yang Guang-Yu, Hanauer Stephen B, Sebag Julien A, Sumagin Ronen
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Department of Urology and Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Gastroenterology. 2021 Jul;161(1):225-238.e15. doi: 10.1053/j.gastro.2021.03.027. Epub 2021 Mar 19.
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.
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.
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 2 mechanism-based translatable therapeutic interventions in sporadic CRC.
肿瘤浸润性中性粒细胞（多形核中性粒细胞[PMN]）是结直肠癌（CRC）的一个显著特征，它们可促进细胞毒性或加重疾病结局。我们最近发现，在急性结肠损伤中，PMN可增加DNA双链断裂（DSB）负担，并通过微小RNA依赖性抑制同源重组（HR）修复来促进基因组不稳定。在本研究中，我们旨在确定在炎症性结肠中，中性粒细胞是否塑造DSB修复反应以影响CRC进展以及对DNA修复靶向治疗的敏感性/抗性。
利用人类散发性CRC活检组织、癌症基因组图谱基因表达分析、肿瘤异种移植模型和小鼠CRC模型，以及对关键DSB修复因子的小分子抑制，来研究DSB修复格局的变化，并识别有无PMN肿瘤浸润情况下CRC的独特反应。
我们发现中性粒细胞在癌细胞中发挥功能二元性，驱动DNA损伤格局的时间调节和DSB的修复。发现PMN通过miR-155依赖性下调RAD51促进低级别CRC中的HR缺陷，从而减弱肿瘤生长。然而，由于DSB积累导致的中性粒细胞介导的基因毒性导致非同源末端连接（NHEJ）的诱导，使晚期CRC得以存活和生长。我们的研究结果确定了一种PMN诱导的HR缺陷型CRC表型，其特征为低RAD51和低Ku70水平，使其易受临床批准的PARP1抑制剂奥拉帕尼诱导的合成致死作用影响。我们进一步确定了一种独特的PMN诱导的HR缺陷型CRC表型，其特征为高Ku70和增强的NHEJ，可通过特异性抑制NHEJ进行治疗靶向。
我们的工作描述了散发性CRC中基于两种机制的可转化治疗干预措施。
