Neutrophils Alter DNA Repair Landscape to Impact Survival and Shape Distinct Therapeutic Phenotypes of Colorectal Cancer.

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.

Distress tolerance in relation to cessation history and smoking characteristics among adult daily smokers.

INTRODUCTION: Distress tolerance (DT) is linked to smoking initiation, maintenance, and difficulty quitting. However, there is a lack of consistency in prior findings on DT's relations with conceptually linked smoking variables, and few studies have examined differences across DT domains. We examined interrelations between cessation history, smoking characteristics, and a full battery of multimethod DT measures. METHODS: We conducted a two-session laboratory assessment with 106 adult, daily smokers with moderate or lower smoking-specific DT, assessed by the Intolerance for Smoking Abstinence Discomfort Questionnaire. Additional DT indices included the Distress Tolerance Scale and four validated behavioral measures (mirror-tracing, serial addition, cold pressor, and breath-holding tasks). Participants reported on cessation history (length and number of prior quit attempts, withdrawal severity at previous attempt) as well as years smoking, cigarettes per day, and nicotine dependence. RESULTS: Withdrawal severity and nicotine dependence were consistently associated with lower self-reported DT, and associations were strongest with perceived tolerance of smoking-specific versus general distress. Length and number of prior quit attempts, years smoking, and cigarettes per day demonstrated a lack of robust associations with behavioral DT measures. CONCLUSIONS: Findings suggest that perceived tolerance of smoking-specific distress may be the most robust indicator of cessation history and smoking characteristics.