Impact of circadian disruption on pancreatic cancer development and progression

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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 combined with the data from Aim 1, will allow the robust identification of genes and pathways to prioritize for future studies. Collectively, the proposed studies will elucidate the potential contributions of circadian disruption to pancreatic cancer development and progression. They will also lay the foundation for future studies that will interrogate the potential mechanisms in depth, thereby leading to novel prevention and therapeutic approaches.