Establishing a mechanistic basis for enhanced tumorigenesis under chronic circadian disruption

项目概要（描述） 昼夜节律协调行为和生理与可预测的日常环境周期。定时 昼夜节律周期的变化主要是由曝光的时间决定的。慢性昼夜节律紊乱 节奏，如在轮班工作或跨时区旅行期间经历的节奏，增加了几种疾病的风险。 人类癌症的类型一些研究表明，暴露于改变的光周期， 概括轮班工人经历的所谓“慢性时差”， 乳腺癌、肝癌和肺癌的工程小鼠模型。我们已经确定了暴露在灯光下 模拟慢性时差反应的时间表增加了KRAS驱动肺的小鼠模型中的肿瘤形成 腺癌此外，我们发现，长期暴露于昼夜节律紊乱的小鼠的肿瘤 表达更高水平的被热应激反应因子HSF1激活的基因。 HSF1已被证明在几个系统中促进肿瘤发生，并且在某些系统中可能是特别致病的。 RAS导致的癌症我们假设慢性昼夜节律紊乱导致HSF 1活性升高， 导致KRASG12D的致癌活性加重和肿瘤发生增加。这项建议会 检查是否需要HSF1来增加KRASG12D驱动的肺肿瘤的形成， 昼夜节律紊乱 在本项目的目标1中，我们将在整个动物中或仅在动物体内使用Hsf1的遗传缺失， 研究其在KrasLSLG12D小鼠中昼夜节律破坏引起的肿瘤发生增加中的作用 （又称Krastm4TyJ）。在本项目的目标2中，我们将使用批量RNA测序，数字细胞仪， 差异节律性的检测，以及携带肿瘤的肺切片的位置条形码测序，以揭示 可能有助于增强肿瘤发生的其他分子机制， 环境对昼夜节律的破坏。

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.