Role of cell cycle withdrawal in restricting pancreatic cancer progression.

细胞周期退出在限制胰腺癌进展中的作用。

• 批准号: 8242551
• 负责人: Gregory David
• 金额: $ 18.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242551
• 关键词: Alleles; Cell Culture System; Cell Cycle; Cell Proliferation; Cells; Data; Disease; Ductal Epithelial Cell; Ectopic Expression; Employee Strikes; Event; Exhibits; Generations; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Histone Deacetylase; Human; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Molecular; Mus; Non-Invasive Lesion; Oncogenic; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Premalignant; Prevention; Proteins; Repression; Resistance; Role; Sampling; Signal Transduction; Staging; Stress; System; Testing; Therapeutic; Tumor Suppressor Proteins; Up-Regulation; Withdrawal; in vivo; mouse model; novel therapeutics; pancreatic neoplasm; prevent; promoter; senescence; therapeutic development; tumor; tumor progression

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma is virtually invariably a fatal disease, and is characterized by invasive and metastatic progression, as well as a striking resistance to conventional therapeutic approaches. Early pancreatic non-invasive lesions, known as pancreatic intraepithelial neoplasia (PanIN) are believed to represent initiating lesions in the generation of PDAC. Importantly, PanINs exhibit very limited proliferation, both in human pancreas and in mouse models of cancer, despite the activation of the mitogenic Ras pathway. The precise molecular pathways that restrict the progression of early PanIN lesions to more aggressive lesions remain for the most part elusive. Identifying and targeting these pathways is likely to represent new therapeutic opportunities for the treatment of pancreatic cancer. Using genetically engineered mice and cells, we have recently demonstrated that the histone deacetylase (HDAC)-associated Sin3B protein is required for cell cycle withdrawal and senescence induced by expression of oncogenic Ras. Importantly, we have demonstrated that Sin3B protein levels strongly increase in early PanIN lesions compared to normal pancreas, but decrease as the tumor progresses. These observations strongly suggest that Ras-driven cell cycle withdrawal, mediated by Sin3B-dependent repression of pro-proliferative genes, halts the progression from premalignant to invasive pancreatic lesions in vivo. In the proposed study, we will examine the molecular mechanisms underlying the lack of proliferation observed in early stage PanINs and its relationship with oncogenic Ras signaling. We will take advantage of the conditional Sin3B allele we have generated in the mouse to assess the contribution of cell cycle exit and senescence as a tumor suppressor mechanism in the pancreas, using physiologically relevant cellular systems and mouse models. Specifically, we propose to: test the hypothesis that a Sin3B-dependent cell cycle withdrawal restricts Ras-induced pancreatic-tumor progression in vivo (Aim 1); and to identify the molecular pathways engaged by Ras activation in pancreatic ductal cells, in a Sin3B-dependent manner (Aim 2). To do so, we will use a physiologically relevant primary ductal cell culture system, and genetically engineered mouse models of pancreatic cancer. PUBLIC HEALTH RELEVANCE: Pancreatic ductal adenocarcinoma is virtually invariably a fatal disease, and is characterized by invasive and metastatic progression, as well as a striking resistance to conventional therapeutic approaches. Early pancreatic non-invasive lesions, known as pancreatic intraepithelial neoplasia (PanIN) are believed to represent initiating lesions in the generation of PDAC. Understanding the molecular events that allow the progression from PanINS to full cancer would provide new therapeutic opportunities in the treatment of pancreatic cancer.

描述（由申请人提供）：胰腺导管腺癌实际上总是一种致命的疾病，其特征是侵袭性和转移性进展，以及对传统治疗方法的显着抵抗。早期胰腺非侵袭性病变，称为胰腺上皮内瘤变 (PanIN)，被认为是 PDAC 生成过程中的起始病变。重要的是，尽管促有丝分裂 Ras 途径被激活，但 PanIN 在人类胰腺和小鼠癌症模型中都表现出非常有限的增殖。限制早期 PanIN 病变进展为更具侵袭性病变的精确分子途径在很大程度上仍然难以捉摸。识别和靶向这些途径可能代表治疗胰腺癌的新治疗机会。 使用基因工程小鼠和细胞，我们最近证明组蛋白脱乙酰酶 (HDAC) 相关的 Sin3B 蛋白是致癌 Ras 表达诱导的细胞周期退出和衰老所必需的。重要的是，我们已经证明，与正常胰腺相比，早期 PanIN 病变中 Sin3B 蛋白水平大幅增加，但随着肿瘤进展而下降。这些观察结果强烈表明，Ras 驱动的细胞周期退出（由 Sin3B 依赖性促增殖基因抑制介导）可阻止体内从癌前病变进展为侵袭性胰腺病变。在拟议的研究中，我们将研究早期 PanIN 中观察到的增殖缺乏的分子机制及其与致癌 Ras 信号传导的关系。我们将利用我们在小鼠中产生的条件 Sin3B 等位基因，使用生理相关的细胞系统和小鼠模型来评估细胞周期退出和衰老作为胰腺肿瘤抑制机制的贡献。具体来说，我们建议：检验 Sin3B 依赖性细胞周期退出限制 Ras 诱导的体内胰腺肿瘤进展的假设（目标 1）；并以 Sin3B 依赖性方式识别胰腺导管细胞中 Ras 激活所涉及的分子途径（目标 2）。为此，我们将使用生理相关的原代导管细胞培养系统和胰腺癌基因工程小鼠模型。 公共健康相关性：胰腺导管腺癌实际上总是一种致命的疾病，其特点是侵袭性和转移性进展，以及对传统治疗方法的显着抵抗。早期胰腺非侵袭性病变，称为胰腺上皮内瘤变 (PanIN)，被认为是 PDAC 生成过程中的起始病变。了解从 PanINS 进展为完全癌症的分子事件将为胰腺癌的治疗提供新的治疗机会。