TGF-beta Signaling in Pancreatic Cancer

描述（由申请人提供）：转化生长因子-？（TGF?）信号通路在胰腺导管腺癌（pancreatic ductal adencarcinoma， PDAC）发病机制中发挥双重作用；抑制肿瘤的早期发展，同时促进晚期癌症的生长。Smad4，中心TGF？Smad4突变在约50%的人类PDAC中发生突变，并且Smad4突变促进小鼠PDAC，与肿瘤抑制功能一致。另一方面，支持TGF？Pathway在促进已建立的癌症生长中的作用包括从人类研究和我们的小鼠模型中观察到的一些结果。具体来说，1)TGF？通路激活与晚期人类PDAC相关，2)阻断TGF？途径抑制人类和小鼠PDAC细胞系的一个亚群的致瘤性。根据我们的初步数据，我们假设TGF-？/Smad4信号a)在早期阶段抑制肿瘤的发生和进展，但b)促进晚期PDAC亚群的恶性生长。因此TGF？信号传导可能对转移性PDAC的一个亚群的治疗有效。本提案描述了一个系统的方法来理解TGF？贯穿胰腺导管肿瘤发生各阶段的通路功能。这些研究将采用改进的小鼠模型，使TGF？体内和体内的信号。我们还将使用药理学方法来解除对这一途径的管制。最后，我们将在已知分子谱的PDAC细胞系中进行高通量测定，以确定能够预测对TGF？途径。具体目标是：(1)确定Smad4调节PDAC前体病变（PanINs）进展和随后肿瘤表型的机制；(2)探索TGF？信号作为晚期PDAC治疗的靶点；(3)测定TGF？促进肿瘤发生的途径成分和TGF？PDAC中的响应性。

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.