Role of cell cycle withdrawal in restricting pancreatic cancer progression.

描述（由申请人提供）：胰腺导管腺癌几乎总是一种致死性疾病，其特征在于侵袭性和转移性进展，以及对常规治疗方法的显著抗性。被称为胰腺上皮内瘤变（PanIN）的早期胰腺非侵入性病变被认为是PDAC产生中的起始病变。重要的是，PanIN在人胰腺和小鼠癌症模型中表现出非常有限的增殖，尽管激活了促有丝分裂Ras途径。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胰腺癌治疗的新治疗机会。 使用基因工程小鼠和细胞，我们最近已经证明，组蛋白脱乙酰酶（HDAC）相关的Sin 3B蛋白是所需的细胞周期退出和致癌Ras的表达诱导的衰老。重要的是，我们已经证明，与正常胰腺相比，Sin 3B蛋白水平在早期PanIN病变中强烈增加，但随着肿瘤进展而降低。这些观察结果强烈表明，Ras驱动的细胞周期退出，介导的Sin 3B依赖性抑制促增殖基因，停止进展，从癌前病变的侵袭性胰腺病变在体内。在这项研究中，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Sin 3B等位基因，使用生理学相关的细胞系统和小鼠模型，评估细胞周期退出和衰老作为胰腺肿瘤抑制机制的贡献。具体而言，我们建议：检验Sin 3B依赖性细胞周期退出限制Ras诱导的胰腺肿瘤体内进展的假设（目标1）;并以Sin 3B依赖性方式鉴定胰腺导管细胞中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的基因工程小鼠模型。

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.