Circadian rhythms are biological processes a period of 24 hours driven by the circadian CLOCK-BMAL1 transcription factor that regulates diurnal variations of cellular metabolism and inflammation signaling. Disruption of the circadian clock has been linked to cancer, but mechanisms of how the clock affects cancer progression are not well understood. We previously shown that oncogenic MYC could disrupt the circadian clock in cancer cells and in vivo in Drosophila and note that analysis of TCGA data indicates widespread mutations in the circadian clock circuitry genes. To address the role of the clock heterogeneity in tumor biology, we chose to study melanomas, which respond to immunotherapy and targeted therapy with varying degrees of therapeutic resistance. In preliminary studies of a panel of 14 patient-derived melanoma cell lines, we found heterogeneity in clock function and increased interferon response genes when the clock is molecularly disrupted in engineered cells. Further we found in a mouse model of melanoma that clock disruption was associated with accelerated tumorigenesis in immunocompetent but not immunocompromised mice. Increased or decreased BMAL1, the central clock component, induced dedifferentiation, rendering mouse melanoma cells immune privileged with altered chemokine expression and resistance to immunotherapy in vivo. Based on our preliminary studies, we hypothesize that functional clock heterogeneity alters cancer cell immunity and contribute variable therapeutic responses. We propose to alter clock function through loss and gain of BMAL1 function in engineered human and mouse melanoma cell lines and determine the molecular mechanisms underlying resistance of melanoma to anti-PD1 treatment. We will use a humanize mouse (Hu-mice) system to study the clock-engineered human melanoma cells in vivo. These findings are expected to contribute novel concepts of therapeutic resistance, biomarkers based on clock biology, and eventual better therapeutic strategies.
Disruption of circadian rhythm, which are biological processes that oscillate with a period of 24 hours, has been linked to increased cancer risk in night-shift workers. Cancer cells can have disrupted cellular circadian clocks that could make them more or less aggressive, or resistant to therapy. This unexplored research area, which is likely to contribute to a better understanding of resistance to standard and immunotherapy, will be the focus of this application, which is expected to provide concepts for better therapeutic strategies.
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