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: 10366975
• 负责人: Selma Masri
• 金额: $ 58.74万
• 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/10366975
• 关键词: APC mutation; ARNTL gene; 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; Pharmacology; Plant Roots; Polyps; Prevention strategy; Reporting; Research; Risk Factors; Role; Sampling; Signal Transduction; Sleep Wake Cycle; Surveys; Survival Rate; System; TP53 gene; Testing; The Cancer Genome Atlas; Time-restricted feeding; Tumor Suppressor Proteins; United States; WNT Signaling Pathway; base; biobank; c-myc Genes; cancer diagnosis; cancer prevention; cell growth regulation; circadian; circadian pacemaker; 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; reconstitution; replication stress; 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.

项目概要/摘要 结直肠癌 (CRC) 是美国第三大确诊癌症。尽管成人 CRC 病例 （55 岁及以上）的发病率有所下降，但 15-40 岁的年轻人中 CRC 的发病率却呈惊人的上升趋势。这是 估计到 2030 年，早发 (EO) 癌症的发病率将惊人地增加 11-12%。 成人 CRC 病例通常存在 Apc 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 Smad4 中的第二次点击。 Apc 突变也见于早发性 CRC（EO- CRC），但据报道，典型的第二次打击驱动路径有所减少。因此，当务之急是 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 EO-CRC 散发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，生物钟是我们体内控制的起搏器 睡眠/觉醒周期、进食、荷尔蒙和其他循环节律。这表明昼夜节律被破坏 时钟可能是 EO 癌症的主要危险因素。为了进一步支持这一想法，临床数据表明时钟 基因在人类结直肠肿瘤中广泛下调，表明时钟的抑制可能是 对于肠上皮细胞的转化很重要。直接解决时钟之间的潜在联系 和 CRC，我们开发了一种新颖的基因小鼠模型来定义生物钟的破坏如何驱动 结直肠癌发病机制。我们的初步数据表明，肠上皮细胞的时钟被破坏 导致息肉形成在统计上显着增加。使用我们的小鼠模型系统，类器官培养 揭示时钟破坏加速了肠上皮的转化。基于这些发现，我们 假设时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 肠道内的不稳定和转化。目标 2 将确定生物钟在调节中的作用 由 EO-CRC 建立的小鼠和人类类器官系统中肠上皮细胞的代谢 患者样本。目标 3 将描述扰乱生物钟的饮食模式如何加速肠道 转变。我们的研究结果具有更广泛的影响，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 以及可能影响肿瘤发生的生活方式因素。