Establishing a mechanistic basis for enhanced tumorigenesis under chronic circadian disruption

建立慢性昼夜节律紊乱下增强肿瘤发生的机制基础

• 批准号: 10608913
• 负责人: Katja A Lamia
• 金额: $ 64.01万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608913
• 关键词: Address; Affect; Animals; Behavior; Biological; Breast Cancer Model; Carcinogens; Cell physiology; Cells; Chronic; Circadian Dysregulation; Circadian Rhythms; Cytometry; Data; Detection; Development; Epidemiology; Exhibits; Exposure to; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Growth; Health; Heat Stress Disorders; Helicobacter pylori; Hour; Incidence; International Agencies; Investigation; Jet Lag Syndrome; K-ras mouse model; KRAS oncogenesis; KRAS2 gene; KRASG12D; Kinetics; Knowledge; Light; Lighting; Link; Location; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Metabolic Diseases; Molecular; Mus; Nuclear; Oncogenic; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Periodicity; Peripheral; Persons; Physiological; Physiology; Play; Probability; Public Health; RAS driven cancer; Research; Resolution; Risk; Role; Schedule; Signal Transduction; Skin Cancer; Source; Stimulus; Stress; System; Testing; Time; Travel; Tumor Burden; Vulnerable Populations; Work; anticancer research; biological adaptation to stress; cancer risk; cancer type; cell type; circadian; circadian pacemaker; design; digital; disorder risk; experience; experimental study; genome-wide; heat shock transcription factor; heat-shock factor 1; in vivo; insight; lung tumorigenesis; malignant stomach neoplasm; mouse model; mutant; nervous system disorder; proteostasis; proteotoxicity; response; shift work; temporal measurement; transcription factor; transcriptome sequencing; transcriptomics; tumor; tumor barcoding and sequencing; tumor microenvironment; tumorigenesis

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.

项目总结(说明) 昼夜节律将行为和生理与可预测的日常环境周期相协调。时间的选择 昼夜节律周期的大小主要由光照时间决定。慢性昼夜节律紊乱 节奏，例如在倒班工作或跨时区旅行时所经历的节奏，会增加几种 人类的癌症类型。一些研究表明，暴露在改变了的光周期中 简而言之，倒班工人经历的所谓“慢性时差”在基因上增强了肿瘤的发生 乳腺癌、肝癌和肺癌的转基因小鼠模型。我们已经确定暴露在光线下 模拟慢性时差的时间表增加KRAS驱动的小鼠肺模型的肿瘤形成 腺癌。此外，我们还发现，暴露在慢性昼夜节律紊乱中的小鼠的肿瘤 表达由热应激反应因子HSF1激活的更高水平的基因。 HSF1已被证明在几个系统中促进肿瘤的发生，并可能在 RAS导致的癌症。我们假设慢性昼夜节律紊乱会导致HSF1活性升高，因此 导致KrasG12D的致癌活性加重，肿瘤形成增加。这项提议将 研究HSF1是否是KrasG12D驱动的肺癌形成增加所必需的 昼夜节律紊乱。 在本项目的目标1中，我们将在整个动物体内或仅在动物体内使用HSF1的基因缺失 肿瘤在KrasLSLG12D小鼠昼夜节律紊乱引起的肿瘤发生增加中的作用 (也就是Krastm4TyJ)。在这个项目的目标2中，我们将使用批量RNA测序、数字细胞术、 检测不同的节律性，并对荷瘤肺切片进行位置条形码排序以揭示 可能有助于增强肿瘤发生的其他分子机制 环境对昼夜节律的干扰。