Neutrophils Modulate DNA Damage Repair to Promote Survival/Progression of Colorectal Cancer
Abstract
Tumor-infiltrating neutrophils are a significant feature of colorectal cancer (CRC), where they can promote cytotoxicity or exacerbate disease outcomes. Leveraging human sporadic CRC biopsies, TCGA gene expression analyses, tumor xenografts and murine CRC models, we reveal that neutrophils exert a functional and phenotypic dualism in cancer cells, driving temporal modulation of the DNA Damage Response. Neutrophils were found to promote homologous recombination (HR)-deficiency in early CRC development by miR155-dependent downregulation of RAD51. Importantly, neutrophil-mediated genotoxicity due to accumulation of double-strand breaks(DSBs) led to the induction of non-homologous end-joining (NHEJ), improving survival and promoting growth of advanced CRC. Importantly, our findings identify distinct HR-deficient and NHEJ-competent CRC therapeutic phenotypes. As such, CRC tumors featuring PMN presence, low RAD51 and low Ku70 levels could be effectively targeted by Olaparib and the resulting synthetic lethality.In contrast, treatment of CRC tumors featuring high Ku70 (and other NHEJ signature genes), indicating heightened NHEJ, should includeNHEJ inhibition as monotherapy or in combination with Olaparib to restore sensitivity to synthetic lethality. Thus, our work delineates two mechanism-based translatable therapeutic interventions in sporadic CRC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2022
- Accession Number
- AD1230233
Entities
People
- Triet M. Bui
Organizations
- Northwestern University