Circadian Clock and Myc-dependent Regulation of Cellular Transformation

生物钟和细胞转化的 Myc 依赖性调节

• 批准号: 10544733
• 负责人: Selma Masri
• 金额: $ 58.73万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544733
• 关键词: APC mutation; ARNTL gene; Acceleration; Address; Adult; Age; Behavioral; Biological Assay; Biological Models; Cell Proliferation; Cells; Circadian Dysregulation; Circadian Rhythms; Circadian gene expression; Clinical; Clinical Data; Code; Colorectal Cancer; Colorectal Neoplasms; Complex; Computer Analysis; Coupled; DNA Damage; Data; Death Rate; Development; Diagnostic Neoplasm Staging; Diet; Dietary Factors; Down-Regulation; Eating; Environmental Risk Factor; Enzymes; Epithelial Cells; Genes; Genetic; Genome; Genome Stability; Genomic Instability; Goals; High Fat Diet; Hormonal; Human; Incidence; Intestinal Polyps; Intestines; Link; Loss of Heterozygosity; Malignant Neoplasms; Maps; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Mutation; Oncogenic; Organoids; Pacemakers; Pathogenesis; Pathway interactions; Patients; Periodicity; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Polyps; Prevention strategy; Proliferating; Reporting; Research; Risk Factors; Role; Sampling; Signal Transduction; Sleep Wake Cycle; Stress; Surveys; Survival Rate; System; TP53 gene; Testing; The Cancer Genome Atlas; Time-restricted feeding; Tumor Suppressor Proteins; United States; WNT Signaling Pathway; biobank; c-myc Genes; cancer diagnosis; cancer prevention; cancer type; cell growth regulation; circadian; circadian pacemaker; circadian regulation; colon cancer patients; colorectal cancer prevention; colorectal cancer treatment; dietary; dietary control; driver mutation; early onset; early onset colorectal cancer; exome sequencing; experimental study; feeding; human data; insight; interdisciplinary approach; intestinal epithelium; knock-down; lifestyle factors; metaplastic cell transformation; mouse model; novel; nutrition; older patient; pharmacologic; reconstitution; response; stable isotope; stemness; targeted treatment; therapy development; transcription factor; transcriptome; tumorigenesis; young adult

PROJECT SUMMARY/ ABSTRACT Colorectal cancer (CRC) is the third most diagnosed cancer in the United States. Though CRC cases in adults (55 and older) have decreased, the incidence of CRC in young adults, ages 15-40, is on an alarming rise. It is estimated that by the year 2030, a staggering 11-12% increase in early-onset (EO) cancers will be observed. Adult cases of CRC typically harbor driver mutations in Apc, a tumor suppressor that regulates Wnt signaling, in addition to second hits in Kras, Braf, p53 and Smad4. Apc mutations are also found in early-onset CRC (EO- CRC), but a decrease in the typical second hit driver pathways has been reported. Therefore, there is an urgent need to better define the root cause of EO-CRC. Moreover, clinical evidence suggests that diet is likely a root underlying cause of the increased incidence in sporadic cases of EO-CRC. Interestingly, dietary challenge and timing of food intake directly impinge on the circadian clock, which is our internal pacemaker that governs sleep/wake cycles, feeding, hormonal and other cyclic rhythms. This suggests that disruption of the circadian clock could be a major risk factor for EO cancers. In further support of this idea, clinical data indicates that clock genes are broadly downregulated in human colorectal tumors, suggesting that suppression of the clock could be important for transformation in the intestinal epithelium. To directly address the potential links between the clock and CRC, we have developed a novel genetic mouse model to define how disruption of the circadian clock drives CRC pathogenesis. Our preliminary data demonstrates that disruption of the clock in the intestinal epithelium drives a statistically significant increase in polyp formation. Using our mouse model system, organoid cultures reveal that clock disruption accelerates transformation in the intestinal epithelium. Based on these findings, we hypothesize that clock disruption impinges on intestinal transformation and rewires cellular metabolism to sustain the heightened demand of hyperproliferative cells. Aim 1 will define how the clock machinery regulates genome instability and transformation in the intestine. Aim 2 will determine the role of the circadian clock in governing metabolism of intestinal epithelial cells in both mouse and human organoid systems, established from EO-CRC patient samples. Aim 3 will delineate how dietary paradigms that disrupt the circadian clock accelerate intestinal transformation. The broader impact of our findings will outline new prevention strategies for eradicating EO-CRC and other cancers that potentially relate to disruption of the circadian clock. Additionally, our long-term goal is to achieve targeted pharmacological approaches to regulate the circadian clock and therefore minimize behavioral and lifestyle factors that potentially impinge on tumorigenesis.

项目总结/摘要 结直肠癌（CRC）是美国第三大诊断癌症。虽然成年人的CRC病例 (55和更年长的人）的发病率下降，但15-40岁的年轻人中CRC的发病率却在惊人地上升。是 据估计，到2030年，早发性（EO）癌症将增加11-12%。 成人CRC病例通常在Apc中携带驱动突变，Apc是一种调节Wnt信号传导的肿瘤抑制因子， 除了Kras、Braf、p53和Smad 4中的第二次命中之外。Apc突变也见于早发性CRC（EO-1）。 CRC），但已报道典型的二次命中驱动途径减少。因此迫切 需要更好地定义EO-CRC的根本原因。此外，临床证据表明，饮食可能是一个根源， 散发性EO-CRC病例发病率增加的根本原因。有趣的是，饮食挑战和 食物摄入的时间直接影响生物钟，生物钟是我们体内的起搏器， 睡眠/觉醒周期、进食、激素和其他周期性节律。这表明昼夜节律的紊乱 生物钟可能是EO癌症的主要危险因素。为了进一步支持这一观点，临床数据表明， 基因在人类结直肠肿瘤中广泛下调，这表明生物钟的抑制可能是 对肠上皮细胞的转化很重要。直接解决时钟和时间之间的潜在联系 和CRC，我们已经开发了一种新的遗传小鼠模型，以确定生物钟的破坏如何驱动 CRC发病机制。我们的初步数据表明，肠上皮细胞中的生物钟中断， 导致息肉形成的统计学显著增加。使用我们的小鼠模型系统， 揭示了生物钟中断加速了肠上皮的转化。基于这些发现，我们 假设生物钟中断影响肠道转化并重新连接细胞代谢以维持 过度增殖细胞的需求增加。目标1将定义时钟机制如何调节基因组 肠内的不稳定和转化。目标2将确定生物钟在管理中的作用 肠上皮细胞在小鼠和人类类器官系统中的代谢，由EO-CRC建立 患者样本。目标3将描述饮食模式如何扰乱生物钟加速肠道 转型我们研究结果的更广泛影响将概述根除EO-CRC的新预防策略 以及其他可能与生物钟紊乱有关的癌症。此外，我们的长期目标是 实现有针对性的药理学方法来调节生物钟，从而最大限度地减少行为 和生活方式因素可能影响肿瘤发生。