E185: The Circadian Clock Exerts Influence on Pancreatic Cancer Collagen Composition

ePoster Abstract Author(s)

Patrick B. Schwartz, MD PhD

Resident
University of Wisconsin Hospitals and Clinics
Madison, Wisconsin, United States

Submitter(s)

Patrick B. Schwartz, MD PhD

Resident
University of Wisconsin Hospitals and Clinics
Madison, Wisconsin, United States

Author(s)

Patrick B. Schwartz, MD PhD

Resident
University of Wisconsin Hospitals and Clinics
Madison, Wisconsin, United States
MN

Manabu Nukaya, PhD

Scientist
Department of Surgery, University of Wisconsin, United States
DL

Desmond Layne, MD

Postdoctoral Fellow
Department of Surgery, University of Wisconsin, United States
KK

Ksenija Korac, PhD

Postdoctoral Fellow
Department of Surgery, University of Wisconsin, United States
MB

Mark Berres, PhD

Bioinformatician
Bioinformatics Resource Center, Biotechnology Center, University of WIsconsin, United States
SR

Sean M. Ronnekleiv-Kelly, MD

Assistant Professor
Department of Surgery, University of Wisconsin, United States

Introduction: Pancreatic ductal adenocarcinoma (PDAC) exhibits circadian dysfunction leading to enhanced carcinogenesis, but the mechanistic drivers remain unknown due to an incomplete picture of how circadian clock distortion contributes to cancer pathology. Previous experiments have focused on assessing gene rhythmicity as a measure of clock functionality. However, recent evidence suggests that non-rhythmic genes may also be clock-coupled. We sought to use an innovative bioinformatics technique that includes rhythmic and non-rhythmic genes regulated by the clock to investigate the clock-coupled pathway differences between normal pancreatic tissue and PDAC.

Methods: We applied LTM, an in silico screen of clock-coupled pathways to four separate RNA sequencing datasets: 1) wildtype C57Bl/6J mouse pancreas 2) PDAC from the Kras^G12D/+; Trp53^R172H/+; Pdx-1 Cre mouse, 3) human normal pancreas and 4) PDAC from the combined TCGA/CPTAC-3 databases. LTM is a computational technique that simulates genome-wide knockdown experiments to infer genes’ influence on circadian clock function. Pathways were assessed with gene set enrichment analysis and targeted genes were compared by normalized absolute LTM values.

Results: We found that normal mouse and human pancreatic clock functionality was associated with expected cell cycle-related pathways (e.g. MITOTIC_METAPHASE_AND_ANAPHASE), while the clock in PDAC was associated with activation of the immune system (TCR_PATHWAY & CD8_TCR_PATHWAY), altered metabolism (METABOLISM_OF_FOLATE_AND_PTERINES), and cancer-related pathways (GASTRIC_CANCER_NETWORK). Concordant with activation of cancer-related pathways the clock was associated with coupling of PI3K. Our prior work suggested that cancer-associated fibroblasts may be the target of clock disruption in the developing PDAC microenvironment. Therefore, we examined the complement of collagen genes for clock-coupling and found that the clock was associated with Type I and VI collagen and the absence of Type IV collagen (Figure 1).

Conclusions: The present study used paired mouse and human datasets to discover non-canonical clock-coupled pathways that might impact PDAC carcinogenesis. We identified changes in clock function between PDAC and normal pancreas that impacted several pathways that are commonly hijacked in cancer. Also, the enhanced cancer-associated fibroblast signatures (e.g., type VI collagens) provide a strong link between the dysregulated clock and collagen changes necessary for the development of desmoplasia and metastases.

Learning Objectives:

Describe the role of the circadian clock in normal pancreas.
Define the result of the loss of normal circadian function for pancreatic cancer.
Describe the effect of clock dysfunction on collagen.