Impact of circadian disruption on pancreatic cancer development and progression

昼夜节律紊乱对胰腺癌发生和进展的影响

• 批准号: 10531625
• 负责人: BRIAN C LEWIS
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531625
• 关键词: ARNTL gene; Acceleration; Address; Affect; Alleles; Cancer Etiology; Carcinogens; Carcinoma; Cessation of life; Chronic; Circadian Dysregulation; Circadian Rhythms; Classification; Credentialing; Cues; Darkness; Data; Development; Diagnosis; Disease; Disease Progression; Disease model; Environment; Environmental Health; Evaluation; Foundations; Future; Gene Expression; Gene Mutation; Genes; Genetic; Genetically Engineered Mouse; Health; Health Hazards; Homeostasis; Human; Incidence; Individual; Intraepithelial Neoplasia; Investigation; KRAS oncogenesis; KRASG12D; Lesion; Light; Lighting; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mental Health; Metabolic; Metabolism; Modeling; Molecular; Mouse Strains; Mus; Mutation; Neoplasm Metastasis; Neurons; Obesity; Outcome; Pacemakers; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Peripheral; Persons; Phase; Play; Prevalence; Prevention; Prevention strategy; Probability; Process; Prognosis; Protocols documentation; Regulation; Research Personnel; Resistance; Role; Series; Societies; Testing; Therapeutic; Time; Tissues; Treatment Protocols; Tumor Promotion; United States; Work; cancer prevention; carcinogenesis; circadian; circadian biology; circadian pacemaker; epidemiology study; genome-wide; improved; in vivo; insight; lung development; mortality; mouse model; novel; pancreas development; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pancreatic tumorigenesis; shift work; single-cell RNA sequencing; statistics; suprachiasmatic nucleus; therapeutically effective; treatment strategy; tumor; tumor initiation; tumor progression

Abstract Shift work with resulting circadian disruption is increasingly recognized as a major environmental health hazard. In view of the prevalence of shift work in Western societies, investigation of the role played by circadian disruption should be assessed in many diseases. In addition to well-demonstrated effects on metabolism/ obesity and mental health, shift work has been classified as a Type 2A “probable carcinogen.” Recent work shows that environmental or genetic disruption of circadian rhythm can promote the development of lung cancer in mouse models of the disease. We seek to conduct similar studies, to assess whether circadian disruption impacts the development and/or progression of pancreatic cancer. It is estimated that pancreatic cancer will claim the lives of almost 48,000 people in 2021, making it the third-leading cause of cancer-related deaths in the United States. The disease carries a very dismal prognosis with median survival of approximately 8 months. This dire prognosis reflects the advanced stage of disease at diagnosis and the resistance of pancreatic cancer to currently employed treatment regimens, underscoring the need for a deeper understanding of the molecular underpinnings of the disease. Such understanding will increase the ability to develop novel effective therapeutic strategies. Given the number of individuals who perform shift work, understanding whether circadian disruption enhances pancreatic tumor initiation and/or progression, and characterizing the factors involved in this process is of great significance. This proposal will therefore directly test the hypothesis that circadian disruption enhances pancreatic cancer development and progression. In the first specific aim, we will test the hypothesis that circadian disruption induced by altered lighting protocols promotes the development of pancreatic cancer precursor lesions called pancreatic intraepithelial neoplasms (PanINs) in the validated FSF-KrasG12D;Pdx1-flp (KF) mouse model. We will further assess whether circadian disruption promotes progression to invasive carcinoma in this model, as well as in the FSF- KrasG12D;Trp53FRT/+;Pdx1-flp (KPF) model. To gain mechanistic insight into how circadian disruption promotes pancreatic tumorigenesis, we will additionally perform metabolic assessments of tumor-bearing mice. We will also subject a subset of tumors to single-cell RNA sequencing to identify gene expression changes that are specifically associated with tumors induced following circadian disruption. In the second aim, we will test the hypothesis that genetic disruption of normal circadian rhythms promotes the development and progression of pancreatic tumors. We will generate compound genetic mouse strains bearing the tumor-promoting Kras and Trp53 alleles in combination with neuron-specific deletion of Bmal1, previously shown to disrupt normal circadian rhythm. Parallel evaluation of metabolic and gene expression changes induced in these mice, when combined with the data from Aim 1, will allow the robust identification of genes and pathways to prioritize for future studies. Collectively, the proposed studies will elucidate the potential contributions of circadian disruption to pancreatic cancer development and progression. They will also lay the foundation for future studies that will interrogate the potential mechanisms in depth, thereby leading to novel prevention and therapeutic approaches.

抽象的 轮班工作所造成的昼夜节律紊乱越来越被认为是主要的环境健康危害。 鉴于西方社会轮班工作的盛行，对昼夜节律紊乱所起的作用进行了调查 除了对代谢/肥胖的良好影响外，还应在许多疾病中进行评估。 心理健康、轮班工作已被列为 2A 类“可能致癌物”。 昼夜节律的环境或遗传破坏可能促进小鼠肺癌的发展 我们寻求进行类似的研究，以评估昼夜节律紊乱是否会影响疾病。 胰腺癌的发生和/或进展 据估计，胰腺癌将夺去生命。 2021 年将有近 48,000 人死于癌症，使其成为美国癌症相关死亡的第三大原因。 该疾病的预后非常差，中位生存期约为 8 个月。 反映了诊断时疾病的晚期阶段以及胰腺癌目前的耐药性 采用的治疗方案，强调需要更深入地了解分子基础 这种疾病的了解将提高开发新的有效治疗策略的能力。 考虑到进行轮班工作的人数，了解昼夜节律紊乱是否会增强 胰腺肿瘤的发生和/或进展，以及表征该过程中涉及的因素非常重要 因此，该提案将直接检验昼夜节律紊乱增强的假设。 胰腺癌的发生和进展。 在第一个具体目标中，我们将测试以下假设：改变照明协议会引起昼夜节律紊乱 促进胰腺癌前体病变（称为胰腺上皮内肿瘤）的发展 (PanINs) 在经过验证的 FSF-KrasG12D;Pdx1-flp (KF) 小鼠模型中我们将进一步评估是否具有昼夜节律。 在该模型以及 FSF-中，破坏促进了侵袭性癌的进展 KrasG12D;Trp53FRT/+;Pdx1-flp (KPF) 模型 深入了解昼夜节律紊乱如何促进。 胰腺肿瘤的发生，我们还将对荷瘤小鼠进行代谢评估。 还对一部分肿瘤进行单细胞 RNA 测序，以确定基因表达变化 与昼夜节律紊乱后诱发的肿瘤特别相关。 在第二个目标中，我们将检验以下假设：正常昼夜节律的遗传破坏会促进 我们将产生具有复合基因的小鼠品系。 促进肿瘤的 Kras 和 Trp53 等位基因与 Bmal1 的神经元特异性删除相结合，之前 显示会扰乱正常的昼夜节律，同时评估诱导的代谢和基因表达变化。 在这些小鼠中，当与目标 1 的数据相结合时，将能够可靠地识别基因和通路 为未来的学习确定优先顺序。 总的来说，拟议的研究将阐明昼夜节律紊乱对胰腺的潜在影响 他们还将为未来的研究奠定基础，以探究癌症的发展和进展。 深入研究潜在机制，从而产生新的预防和治疗方法。