Role of cell cycle withdrawal in restricting pancreatic cancer progression.

描述(申请人提供)：胰腺导管腺癌几乎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著抵抗。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发生的始发病变。重要的是，Panins在人类胰腺和小鼠癌症模型中表现出非常有限的增殖，尽管有丝分裂的RAS途径被激活。限制早期Panin病变进展为更具侵袭性的病变的确切分子途径在很大程度上仍然难以捉摸。识别和靶向这些通路可能代表着胰腺癌治疗的新的治疗机会。 利用基因工程小鼠和细胞，我们最近证明了组蛋白脱乙酰酶(HDAC)相关的Sin3B蛋白是由致癌RAS的表达引起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PAIN病变中Sin3B蛋白水平显著升高，但随着肿瘤的进展，SIN3B蛋白水平下降。这些观察有力地表明，RAS驱动的细胞周期退出，通过依赖Sin3B对促增殖基因的抑制，在体内阻止了从癌前病变到侵袭性胰腺病变的进展。在这项拟议的研究中，我们将研究早期Panins缺乏增殖的分子机制及其与致癌RAS信号的关系。我们将利用我们在小鼠中产生的条件性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。具体地说，我们建议：验证依赖于Sin3B的细胞周期退出限制RAS诱导的体内胰腺肿瘤进展的假设(目标1)；并以依赖Sin3B的方式确定胰腺导管细胞中RAS激活所涉及的分子通路(目标2)。为此，我们将使用生理上相关的原代导管细胞培养系统，以及胰腺癌的基因工程小鼠模型。 公共卫生相关性：胰腺导管腺癌几乎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著抵抗。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发生的始发病变。了解导致胰腺癌向全癌进展的分子事件将为胰腺癌的治疗提供新的治疗机会。

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.