Circadian Disruption in Pancreatic Cancer
Abstract
The objective of this proposal is to understand the extent to which circadian rhythm disruption contributes to PDAC pathogenesis. We hypothesize that circadian disruption enhances PDAC development and progression, and that PDAC arising in the setting of circadian disruption (PDACCD) is biologically distinct compared with PDAC developing under normal circadian conditions (PDACNC). We have used novel models and techniques to test our hypothesis. At final analysis, we have found that: i) chronic jetlag (disruption of circadian rhythm) enhances development and pre-cancer tumor (PanIN-2) formation in the pancreas in vivo; and ii) core clock gene knockout (Bmal1) in established pancreas cancer cells (abolishes the circadian clock) causes heightened tumor progression compared to Bmal1 wild-type pancreas cancer cells in vivo. This is remarkable considering the already aggressive nature of the Kras- Tp53-mutant pancreas cancer cells. Finally, we aimed to understand the biological differences between circadian intact and circadian disrupted pancreatic cancer using single-cell RNA sequencing and analysis. Long-term studies will focus on mechanism by which knockout of the clock in pancreas cancer causes a more aggressive phenotype, which will have direct therapeutic implications for development of novel therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2023
- Accession Number
- AD1201622
Entities
People
- Sean Ronnekleiv-kelly
Organizations
- University of Wisconsin–Madison