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Dissertation Defense: Investigating the Interaction Between the Mammalian Circadian Clock and Extracellular Vesicles in the Progression of Pancreatic Cancer

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Jonathan Church
Dissertation Defense

Investigating the Interaction Between the Mammalian Circadian Clock and Extracellular Vesicles in the Progression of Pancreatic Cancer

Jonathan Church

Graduate Student, Translational Biology, Medicine, and Health
Graduate Research Assistant, Finkielstein Lab, Fralin Biomedical Research Institute at VTC
Sept. 5, 2025, at 10 a.m.
2 Riverside, Room R3012
Visit the Finkielstein Lab

More About the Candidate and Project

Education

Virginia Tech, Translational Biology, Medicine, and Health, Ph.D. Candidate

Marshall University, B.S., Biochemistry

Training

Graduate Research Assistant, Finkielstein Lab, Fralin Biomedical Research Institute at VTC

Mentors

Carla Finkielstein, Ph.D., Professor, Fralin Biomedical Research Institute at VTC

Committee Members

  • Joshua Drake, Ph.D., Assistant Professor, Department of Human Nutrition, Foods, and Exercise, College of Agriculture and Life Sciences, Virginia Tech
  • Shihoko Kojima, Ph.D., Associate Professor, Department of Biological Sciences, College of Science, Virginia Tech
  • Robert Gourdie, Ph.D., Professor, Director, Center for Vascular and Heart Research, Fralin Biomedical Research Institute at VTC
  • Nikolaos Dervisis, DVM, Ph.D., Associate Professor, Department of Veterinary Clinical Sciences, Purdue University College of Veterinary Medicine

Publications

Church, J., Kadukhina, E., Aiello, I. et al. Circadian Regulation of Extracellular Vesicle Biogenesis, Composition, and Release. npj Biol Timing Sleep. In press.

Presentations

Church, J. CycliCx Peptide Alters Cx43 Localization and Inhibits SMC Proliferation. Presentation at: Fralin Biomedical Research Institute. Roanoke, VA. March 2021

Church, J. Mammalian Circadian Oscillations in Response to DNA Damage. Presentation at: Fralin Biomedical Research Institute. Roanoke, VA. May 2021.

Church, J. Timing is Key: Emerging Roles of Extracellular Vesicles in Pancreatic Cancer Cachexia. Presentation at: Fralin Biomedical Research Institute. Roanoke, VA. January 2023 (Research in Progress Seminar)

Church, J. Extracellular Vesicles Mediate Circadian Deregulation and Myotube Atrophy in Pancreatic Cancer Cachexia. Presentation at: FBRI Annual Retreat. Hot Springs, VA. June 2023 (FBRI Annual Retreat)

Church, J. Presentation at: Fralin Biomedical Research Institute. Roanoke, VA. December 2023. (TBMH Symposium)

Church, J. Secreted Factors from PDAC Cells Promote Circadian Deregulation, Atrophy, and Migration. Presentation at: Virginia Tech. Blacksburg, VA. February 2024. (College of Science 21st Annual Research Day)

Church, J. Secreted Factors from Pancreatic Cancer Promote Circadian Deregulation and Myotube Atrophy. Presentation at: Society for Research on Biological Rhythms Annual Meeting. San Juan, PR. May 2024. (SRBR) (Oral Presentation and Poster Presentation)

Church, J. Secreted Factors from Pancreatic Cancer Cells Promote Circadian Dysregulation and Atrophy. Presentation at: Vanderbilt University, Nashville TN. May 2025. (Oral Presentation and Poster Presentation)

Church, J. Secreted Factors from Pancreatic Cancer Cells Promote Circadian Dysregulation and Atrophy. Presentation at: VT FBRI Cancer Research Center Symposium. Roanoke, VA. June 2025.

  • 1st Place, HS&T Hokie Pitch Commercialization Competition, 2020
  • Recipient of the Virginia Academy of Science Mary Louise Olds Andrews Award for Cancer Research, 2023

About this Dissertation

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival of <10%. The poor outcome in PDAC patients is due, in part, to high rates of metastasis and the development of cachexia, a multi-system metabolic disorder characterized by significant weight loss, systemic inflammation, and muscle atrophy. While previous studies have suggested that circadian clock dysregulation is associated with worse overall outcomes in cancer patients, the role of circadian dysregulation in muscle atrophy in the context of pancreatic cancer is not well understood. Church, mentored by Carla Finkielstein, hypothesized that PDAC-derived extracellular vesicles (EVs) disrupt circadian-controlled homeostasis to further drive PDAC progression and muscle atrophy. Church's findings show that PDAC-derived EVs are capable of inducing circadian dysregulation of cells in vitro. Using a real-time bioluminescence reporter system, the lab found that NIH3T3 BMAL:Luc fibroblasts treated with secreted factors from PDAC cells exhibited an altered circadian period. Accordingly, gene expression analysis revealed disruption of core clock transcripts in NIH3T3 fibroblasts and C2C12 myotubes, including BMAL1 and PER2, in response to PDAC-derived conditioned media. The lab next sought to determine the role of PDAC-EVs in muscle cells, and found that treatment with secreted factors from PDAC cells was sufficient to induce circadian dysregulation and myotube atrophy in vitro. To further investigate the role of EVs in circadian dysregulation and atrophy, EVs were collected and RNA-seq performed to identify candidate miRNAs that contribute to circadian dysregulation and atrophy. The study's results show a time-dependent variability in the number of EVs and their miRNA composition. Cells were then transfected with candidate miRNA mimics and the effects on the circadian clock and muscle cell function were investigated. Several miRNAs were found to either alter the circadian period or induce myotube atrophy. Together, these findings provide valuable insight into the role of PDAC-derived EVs in circadian dysregulation, cellular migration, and myotube atrophy in the context of pancreatic cancer. A better understanding of the relationship between EVs, circadian dysregulation, and pancreatic cancer could lead to the identification of novel EV-based biomarkers for early detection of pancreatic cancer or risk of developing cachexia.