# Defining the Role of the Cancer Circadian Clock in Tumor Immunity and Tumorigenesis

> **NIH NIH R01** · WISTAR INSTITUTE · 2022 · $363,222

## Abstract

Project Summary
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.

## Key facts

- **NIH application ID:** 10317112
- **Project number:** 5R01CA051497-30
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** CHI V. DANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $363,222
- **Award type:** 5
- **Project period:** 1990-01-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317112

## Citation

> US National Institutes of Health, RePORTER application 10317112, Defining the Role of the Cancer Circadian Clock in Tumor Immunity and Tumorigenesis (5R01CA051497-30). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10317112. Licensed CC0.

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