Neutrophils modulate DNA Damage Repair to promote survival/progression of colorectal cancer

Project: Research project

Project Details

Description

Immune cells termed neutrophils are the most abundant white blood cells in our body, and serve to protect our body against invading pathogens. However, when neutrophils accumulate in tissue, they can also cause recurring injury/ inflammation to the cells of the gastro-intestinal tract. The resulting chronic inflammation in the colon and the subsequent neutrophil infiltration are the hallmarks of Inflammatory Bowel Diseases (IBD) and Colorectal Cancer (FY19 PRCRP Topic Area).
As such, excessive presence of neutrophils in colonic tissues of IBD patients is highly predictive of heightened disease activity and increased likelihood of Colorectal Cancer. Furthermore, tissue accumulation of neutrophils in the tumor microenvironment is often associated with stage III and IV Colorectal Cancer. While there is no doubt that neutrophil-induced inflammation in the gastro-intestinal tract is a key factor that facilitates these disorders, it is still not clear how these cells induce tissue injury. Even less is known of how neutrophils might promote Colorectal Cancer development.
Genomic instability as a defining feature of cancer cells is manifested through the continual changes in the cancer genome driven by accumulation of mutations and deregulation of DNA Repair. It is common that a major portion of cancers manifest a loss of one or more DNA repair pathways and become heavily reliant on the remaining pathways to resolve DNA breaks and maintain survival. The findings in our recent publication and unpublished work suggest that neutrophils may drive cancer progression in IBD tissue by suppressing the “good” DNA repair mode (namely Homologous Recombination) and likely pushing the repair machineries toward the “bad” DNA repair mode (namely Non-Homologous End-Joining), which is much faster yet highly mutagenic and carcinogenic. As a result, we seek to elucidate whether neutrophils facilitate the transition from “good” to “bad” DNA Repair, creating an optimal condition where cancerous cells with unstable genome can rapidly repair DNA breaks, survive, and divide effectively. To this end, we uniquely define a role for neutrophils in promoting IBD-related colon cancer development.
StatusActive
Effective start/end date9/1/208/31/22

Funding

  • U.S. Army Medical Research and Materiel Command (W81XWH-20-1-0452)

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