Establishing a mechanistic basis for enhanced tumorigenesis under chronic circadian disruption

PROJECT SUMMARY (DESCRIPTION) Circadian rhythms coordinate behavior and physiology with predictable daily environmental cycles. The timing of circadian cycles is primarily determined by the timing of light exposure. Chronic disruption of circadian rhythms, such as that experienced during shift work or travel across time zones, increases the risk of several types of cancer in people. A handful of studies has shown that exposure to altered light cycles designed to recapitulate so-called “chronic jet lag” experienced by shift workers enhances tumorigenesis in genetically engineered mouse models of breast, liver, and lung cancers. We have established that exposure to a lighting schedule that mimics chronic jet lag increases tumor formation in a mouse model of KRAS-driven lung adenocarcinoma. Furthermore, we found that tumors from mice exposed to chronic circadian disruption express higher levels of genes that are activated by the heat stress response factor, HSF1. HSF1 has been shown to facilitate tumorigenesis in several systems, and may be particularly pathogenic in RAS-driven cancers. We hypothesize that chronic circadian disruption causes elevated activity of HSF1, thus leading to aggravated oncogenic activity of KRASG12D, and increased tumorigenesis. This proposal will examine whether HSF1 is required for increased formation of KRASG12D-driven lung tumors in response to circadian disruption. In Aim 1 of this project, we will use genetic deletion of Hsf1 either throughout the animal or exclusively within tumors to investigate its role in increased tumorigenesis caused by circadian disruption in KrasLSLG12D mice (a.k.a. Krastm4TyJ). In Aim 2 of this project, we will use a combination of bulk RNA sequencing, digital cytometry, detection of differential rhythmicity, and location-barcoded sequencing of tumor-bearing lung sections to reveal additional molecular mechanisms that could contribute to enhanced tumorigenesis in response to environmental disruption of circadian rhythms.