Role of TGFBeta alterations in pancreatic cancer

描述（由申请人提供）：胰腺导管腺癌（PDAC）患者的预后仍然很差，5年生存率低于5%。因此，深入了解PDAC的侵袭性和耐药性的分子机制，将为新的分子靶向治疗提供基础。为此，我们在这里首次表明，有一个动态的相互作用之间的TGF？和STAT 3活性，这有助于PDAC的侵袭性，靶向这些途径可以阻断侵袭并增强对化疗的敏感性。肿瘤进展的标志之一是TGF？从肿瘤抑制到肿瘤促进的信号传导。这个看似矛盾的TGF？正在对信令进行广泛的调查。转化生长因子通过Smad依赖性和Smad非依赖性途径的信号。我们的研究表明，TGF？在PDAC中需要Smad信令。然而，超过一半的PDAC具有Smad 4基因的等位基因缺失或失活突变。此外，在肿瘤细胞，拥有完整的Smad组件，致癌信号可以减弱Smad信号或改变TGF？转录应答以有利于肿瘤促进。我们发现STAT 3在PDAC中是组成性激活的，并且Smads和STAT 3通路之间存在相互的负调节。在Smad 4完整的细胞，敲低STAT 3增强Smad信号和抑制TGF？介导的运动和侵袭。在Smad 4缺陷的PDAC细胞，STAT 3活性合作，并需要TGF？诱导运动和侵袭。我们的初步结果还表明，STAT 3在用吉西他滨和EGFR激酶抑制剂治疗的PDAC中保持活化。阻断TGF？/ STAT 3轴阻止侵袭并增强对吉西他滨的敏感性。我们的中心假设是PDAC中的致癌性改变引起异常的TGF？/ STAT 3轴在功能上与侵袭性和对化疗的抗性相关。我们将通过完成以下目标来检验这一假设。目标1。确定STAT 3在调节Smad信号传导中的作用，并确定这是否影响PDAC中的肿瘤进展。目标2.确定STAT 3活性和Smad 4非依赖性TGF？信号传导在肿瘤进展中起作用。目标3。确定是否以TGF？/ STAT 3轴改善PDAC的治疗。 这些研究的完成将进一步确定TGF？以及这些相互作用在PDAC的侵袭性和对常规疗法的反应中所起的作用。最终，这些研究的成功结果可能为新的临床试验提供基础。 公共卫生相关性：胰腺癌是美国癌症死亡的第四大原因，五年生存率低于5%。本申请中提出的研究将调查TGF 2和STAT 3的相互作用在胰腺癌的侵袭特性和对化疗的抗性中所起的作用。这些研究包括靶向TGF？/ STAT 3轴，如果成功，应该为临床试验提供支持。

DESCRIPTION (provided by applicant): The prognosis of patients with pancreatic ductal adenocarcinomas (PDAC) remains dismal with a five-year survival of less than 5%. It is hoped that understanding the molecular mechanisms contributing to the invasive nature and the resistance of PDAC to chemotherapy will provide the bases for new molecular-targeted therapies. To this end, we show here for the first time that there is a dynamic interaction between TGF? and STAT3 activities, which contribute to the invasiveness of PDAC and that targeting these pathways may block invasion and enhance sensitivity to chemotherapy. One of the hallmarks of tumor progression is a switch of TGF? signaling from tumor suppression to tumor promotion. This seemingly paradoxical aspect of TGF? signaling is under extensive investigation. TGF? signals through both Smad-dependent and Smad-independent pathways. Our studies indicate that anti-invasive functions of TGF? in PDAC require Smad signaling. However, more than half of PDACs possess allelic deletion or inactivating mutations of the Smad4 gene. Moreover, in tumor cells that possess intact Smad components, oncogenic signals can attenuate Smad signaling or alter TGF? transcriptional responses to favor tumor promotion. We found that STAT3 was constitutively activated in PDAC and that there is reciprocal negative regulation between Smads and STAT3 pathways. In Smad4 intact cells, knocking down STAT3 enhanced Smad signaling and inhibited TGF? mediated motility and invasion. In Smad4 deficient PDAC cells, STAT3 activity cooperates with and is required for TGF? induced motility and invasion. Our preliminary results also suggest that that STAT3 remains activated in PDAC treated with Gemcitabine and EGFR-kinase inhibitors. Blocking TGF?/STAT3 axis prevented invasion and enhanced sensitivity to Gemcitabine. Our central hypothesis is that oncogenic alterations in PDAC cause an aberrant TGF?/STAT3 axis that is functionally linked to both invasiveness and resistance to chemotherapy. We will test this hypothesis by completing the following aims. Aim 1. Determine the role of STAT3 in regulating Smad signaling and determine whether this influences tumor progression in PDAC. Aim 2. Determine the role that cross talk between STAT3 activity and Smad4-independent TGF? signaling plays in tumor progression. Aim 3. Determine whether targeting the TGF?/STAT3 axis improves therapy of PDAC. The completion of these studies will further define the molecular and functional relationship between TGF? and STAT3 and the role these interaction play in the invasiveness and response of PDAC to conventional therapies. Ultimately, a successful outcome of these studies may provide the bases for new clinical trials. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth leading cause of cancer deaths in the United States with a five-year survival rate of less than 5%. The studies proposed in the current application will investigate the role that interaction of TGF2 and STAT3 play in the invasive properties and resistance of pancreatic cancer to chemotherapy. These studies include pre-clinical assessment for targeting the TGF?/STAT3 axis and if successful should provide support for clinical trials.