Neutrophils Alter DNA Repair Landscape to Impact Survival and Shape Distinct Therapeutic Phenotypes of Colorectal Cancer
Neutrophils Alter DNA Repair Landscape to Impact Survival and Shape Distinct Therapeutic Phenotypes of Colorectal Cancer
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DOI：
10.1053/j.gastro.2021.03.027
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发表时间：
2021-06-23
期刊：
影响因子：
29.4
通讯作者：
Sumagin, Ronen
中科院分区：
文献类型：
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作者：
Bui, Triet M.;Butin-Israeli, Veronika;Sumagin, Ronen
背景与目的：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）的一个突出特征，它们可以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，中性粒细胞可以增加DNA双链断裂（DSB）的负担，并通过microRNA依赖性抑制同源重组（HR）修复促进基因组不稳定性。在这项研究中，我们的目的是确定是否在发炎的结肠，中性粒细胞形状的DSB修复反应，以影响CRC的进展和敏感性/耐药DNA修复靶向治疗。方法：利用人类散发性CRC活检、癌症基因组图谱基因表达分析、肿瘤异种移植物和小鼠CRC模型以及关键DSB修复因子的小分子抑制来研究DSB修复景观的变化，并鉴定具有/不具有PMN肿瘤浸润的独特CRC应答。研究结果：我们揭示了中性粒细胞在癌细胞中发挥功能的双重性，驱动DNA损伤景观和DSB分辨率的时间调制。发现PMN通过miR-155依赖性下调RAD 51促进低级别CRC中的HR缺陷，从而减弱肿瘤生长。然而，由于DSB的积累导致的嗜酸性粒细胞介导的遗传毒性导致非同源末端连接（NHEJ）的诱导，允许晚期CRC的存活和生长。我们的研究结果确定了PMN诱导的HR缺陷型CRC表型，具有低RAD 51和低Ku 70水平，使其对临床批准的PARP 1抑制剂奥拉帕尼诱导的合成致死性敏感。我们进一步鉴定了一种独特的PMN诱导的HR缺陷型CRC表型，其特征在于高Ku 70和升高的NHEJ，其可以通过特异性抑制NHEJ进行治疗靶向。结论：我们的工作描绘了2个机制为基础的可翻译的治疗干预散发性结直肠癌。
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.