ABSTRACT
Colorectal cancer (CRC) is the third most diagnosed cancer in the United States. With increasing public
knowledge of cancer risk factors and screening, the incidence of CRC has steadily decreased in individuals over
the age of 50 over the last several decades. However, the incidence of CRC in younger populations has been
on the rise. Individuals under the age of 50 are increasingly afflicted by light-at-night exposure, night-shift work,
and erratic eating patterns, which are known to disrupt the circadian clock. Importantly, disruption of circadian
rhythms is a known risk factor for CRC. Therefore, it is likely that disruption of the circadian clock is a contributing
factor for the alarming increase in early-onset CRC cases. This emerging link between the circadian clock and
cancer has enormous potential for cancer prevention strategies. While causal links are clear, the underlying
mechanism of how the circadian clock impinges on antitumor immunity to create a permissive environment for
tumorigenesis is unknown. The goal of this project is to understand how both genetic and environmental circadian
clock disruption alter the immune landscape to promote tumorigenesis. Our preliminary findings suggest that
disruption of the circadian clock promotes inflammation and alters host immunity. Based on these findings, we
hypothesize that clock disruption promotes inflammation to create an immunosuppressive
microenvironment suitable for cancer initiation and progression. This central hypothesis will be addressed
with the following Specific Aims. Aim 1 will determine how clock disruption alters the in vivo immune landscape
through the activation of MDSCs and the suppression of cytotoxic CD8+ T cells. Aim 2 will define the molecular
mechanism for how clock disruption impacts host immunity to accelerate tumorigenesis through the Wnt
signaling pathway and MYC. The outcome of our findings will define the mechanistic underpinning linking
disruption of the circadian clock to altered host anti-tumor immunity. The long-term goal of this study is to improve
cancer prevention and treatment through lifestyle and pharmacological manipulation of the link between the
circadian clock and the immune system.