Neutrophils Modulate DNA Damage Repair to Promote Survival/Progression of Colorectal Cancer
Abstract
How the US Department of Defense (DoD) Horizon Award supports the Principal Investigator (PI) career development: The PI’s career goal is to become a leading scientist in the field of cancer genomic instability, and to understand how this tumorigenic process is regulated in different cancer types, particularly Colorectal Cancer (CRC), which is among the Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program’s (PRCRP’s) Topic Areas. The proposed study is highly relevant to the PI’s research interest and embodies a large portion of the PI’s PhD dissertation. The researcher development plan has thus been tailored by the research mentor and co-mentor to expand the PI’s knowledge on the biology of CRC, and to assist the PI in acquiring essential techniques, including DNA damage foci imaging, biochemical/genetic assays, and relevant injury/cancer models, that are required to answer complex biological questions emerged during this proposal and beyond. Extensive mentoring by leading scientists in the field of CRC and access to valuable technical/clinical resources at Northwestern University and Hospitals will ensure the PI’s scientific development in a clinical-oriented manner. Support from DoD will enable the PI to fully execute all the proposed experiments within the scope of the study and further allow him to explore other relevant aspects pertaining to the current project, including PMN interactions with circulating tumor cells and PMN activity on tumor vascularization via live imaging techniques. The PI’s future research goal is to develop innovative imaging/biosensor systems that allow tracking in real time of the induction of DNA damage and the changes in genome integrity. This could help determine at what point genomic instability in developing tumors occurs and becomes intolerable and, as such, help physicians adjust cancer therapeutics appropriately. As such, the funding from the Horizon Award will be instrumental in setting the first stage for the PI’s career advancement and enabling him to accomplish his career and research goals as an independent junior investigator. Lay summary. 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 CRC (FY19 PRCRP Topic Areas). As such, excessive presence of neutrophils in colonic tissues of IBD patients is highly predictive of heightened disease activity and increased likelihood of CRC. Furthermore, tissue accumulation of neutrophils in the tumor microenvironment is often associated with stage III and IV CRC. 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 CRC 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
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010452
Entities
People
- Triet M. Bui
Organizations
- Northwestern University
- United States Army