TGF-beta Signaling in Pancreatic Cancer

性状（申请人提供）：转化生长因子-？(TGF?)信号通路在胰腺导管腺癌（PDAC）的发病机制中起双重作用：抑制肿瘤发展的早期阶段，同时促进晚期癌症的生长。Smad 4是一个中心TGF？在约50%的人PDAC中，Smad 4通路效应子突变，并且Smad 4突变促进小鼠中的PDAC，与肿瘤抑制功能一致。另一方面，证据支持TGF？pathway在促进已建立的癌症生长中的作用包括来自人类研究和我们的小鼠模型的许多观察结果。具体而言，1）TGF？通路活化与晚期人PDAC相关，和2）阻断TGF？在一些实施方案中，PDAC通路抑制人和小鼠PDAC细胞系亚组的致瘤性。根据我们的初步数据，我们假设TGF-？/ Smad 4信号传导a）在早期阶段抑制肿瘤发生和进展，但B）促进晚期PDAC亚群的恶性生长。因此，抑制剂的TGF？信号传导可能在转移性PDAC的子集的治疗中有效。该提案描述了一个系统的方法来了解TGF？在胰腺导管肿瘤发生的每个阶段，这些研究将采用完善的小鼠模型，使时间调节激活和失活的TGF？体内和体内信号传导。我们还将使用药理学方法来解除对该途径的管制。最后，我们将进行高通量测定PDAC细胞系与已知的分子概况，以确定标记物能够预测对TGF？通路本研究的主要目的是：（1）明确Smad 4调控PDAC前体病变（PanINs）进展和继发肿瘤表型的机制;（2）探讨TGF？信号传导作为治疗晚期PDAC的靶点;（3）测定TGF？有助于肿瘤发生和定义TGF？PDAC中的响应。 与公共卫生的相关性：PDAC是美国癌症死亡率的第四大原因，对所有现有疗法都有抗药性。我们的研究将定义TGF？在整个PDAC进展的过程中的信号传导，从而提供洞察该途径作为药物靶点的潜力。 公共卫生相关性：TGF β通路被认为是一个很好的药物靶点，因为在许多晚期癌症（包括PDAC）中观察到的活性增加。虽然许多制药公司已经开发出特异性抗TGF β药物，但由于该途径在限制癌症发生中的相反作用，它们的使用变得复杂。我们提出的实验将直接研究TGF-β信号在PDAC进展的不同阶段的作用。详细了解这种生物化学途径的改变如何影响肿瘤发生，将有助于决定如何在患者中使用这些药物与其疾病的阶段和突变特征有关。

DESCRIPTION (provided by applicant): The transforming growth factor-? (TGF?) signaling pathway appears to play dual roles in pancreatic ductal adenocarcinoma (PDAC) pathogenesis; restraining the early stages of tumor development while promoting the growth of advanced cancers. Smad4, a central TGF? pathway effector, is mutated in ~50% of human PDAC, and Smad4 mutations promote PDAC in mice, consistent with a tumor suppressor function. On the other hand, evidence supporting the TGF? pathway's role in promoting growth of established cancers includes a number of observations from human studies and from our mouse models. Specifically, 1) TGF? pathway activation is associated with advanced human PDAC, and 2) blockade of the TGF? pathway inhibits tumorigenicity of a subset of human and mouse PDAC cells lines. Based on our preliminary data, we hypothesize that TGF-?/Smad4 signaling a) restrains tumor initiation and progression at early stages but b) promotes the malignant growth of a subset of advanced PDAC. Hence inhibitors of TGF? signaling are likely to be effective in the treatment of a subset of metastatic PDAC. This proposal describes a systematic approach to understanding TGF? pathway function throughout each stage of pancreatic ductal tumorigenesis. These studies will employ refine mouse models that enable temporally regulated activation and inactivation of TGF? signaling in vivo and in vivo. We will also use pharmacological approaches to deregulate the pathway. Finally, we will conduct high-throughput assays in PDAC cell lines with known molecular profiles to define markers able to predict responsiveness to TGF? pathway. The Specific Aims are (1) Define the mechanisms by which Smad4 regulates progression of PDAC precursor lesions (PanINs) and the phenotypes of ensuing tumors; (2) Explore TGF? signaling as a target for treatment in advanced PDAC; (3) Determine TGF? pathway components that contribute to tumorigenesis and define molecular markers of TGF? responsiveness in PDAC. Relevance to public health: PDAC is the fourth leading cause of cancer mortality in the United States and is resistant to all existing therapies. Our studies will define the biological roles played by TGF? signaling throughout the course of PDAC progression and thereby provide insight into the potential of this pathway as a drug target. PUBLIC HEALTH RELEVANCE: The TGFbeta pathway is thought to be a good drug target based on the increased activity observed in many advanced cancers including PDAC. While a number of pharmaceutical companies have developed specific anti-TGFbeta drug, their use is complicated by the opposing role of the pathway in limiting cancer initiation. Our proposed experiments will directly investigate the role of TGF-beta signaling at different stages of PDAC progression. The detailed understanding of how alterations in this biochemical pathway affect tumorigenesis will inform help in deciding how to use these drugs in patients in relation to the stage and mutational profile of their disease.