# Impact of circadian disruption on pancreatic cancer development and progression

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $209,375

## Abstract

Abstract
Shift work with resulting circadian disruption is increasingly recognized as a major environmental health hazard.
In view of the prevalence of shift work in Western societies, investigation of the role played by circadian disruption
should be assessed in many diseases. In addition to well-demonstrated effects on metabolism/ obesity and
mental health, shift work has been classified as a Type 2A “probable carcinogen.” Recent work shows that
environmental or genetic disruption of circadian rhythm can promote the development of lung cancer in mouse
models of the disease. We seek to conduct similar studies, to assess whether circadian disruption impacts the
development and/or progression of pancreatic cancer. It is estimated that pancreatic cancer will claim the lives
of almost 48,000 people in 2021, making it the third-leading cause of cancer-related deaths in the United States.
The disease carries a very dismal prognosis with median survival of approximately 8 months. This dire prognosis
reflects the advanced stage of disease at diagnosis and the resistance of pancreatic cancer to currently
employed treatment regimens, underscoring the need for a deeper understanding of the molecular underpinnings
of the disease. Such understanding will increase the ability to develop novel effective therapeutic strategies.
Given the number of individuals who perform shift work, understanding whether circadian disruption enhances
pancreatic tumor initiation and/or progression, and characterizing the factors involved in this process is of great
significance. This proposal will therefore directly test the hypothesis that circadian disruption enhances
pancreatic cancer development and progression.
In the first specific aim, we will test the hypothesis that circadian disruption induced by altered lighting protocols
promotes the development of pancreatic cancer precursor lesions called pancreatic intraepithelial neoplasms
(PanINs) in the validated FSF-KrasG12D;Pdx1-flp (KF) mouse model. We will further assess whether circadian
disruption promotes progression to invasive carcinoma in this model, as well as in the FSF-
KrasG12D;Trp53FRT/+;Pdx1-flp (KPF) model. To gain mechanistic insight into how circadian disruption promotes
pancreatic tumorigenesis, we will additionally perform metabolic assessments of tumor-bearing mice. We will
also subject a subset of tumors to single-cell RNA sequencing to identify gene expression changes that are
specifically associated with tumors induced following circadian disruption.
In the second aim, we will test the hypothesis that genetic disruption of normal circadian rhythms promotes the
development and progression of pancreatic tumors. We will generate compound genetic mouse strains bearing
the tumor-promoting Kras and Trp53 alleles in combination with neuron-specific deletion of Bmal1, previously
shown to disrupt normal circadian rhythm. Parallel evaluation of metabolic and gene expression changes induced
in these mice, when com...

## Key facts

- **NIH application ID:** 10373645
- **Project number:** 1R21ES031802-01A1
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** BRIAN C LEWIS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $209,375
- **Award type:** 1
- **Project period:** 2021-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10373645

## Citation

> US National Institutes of Health, RePORTER application 10373645, Impact of circadian disruption on pancreatic cancer development and progression (1R21ES031802-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10373645. Licensed CC0.

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