Role of TGFBeta alterations in pancreatic cancer

描述(申请人提供)：胰腺导管腺癌(PDAC)患者的预后仍然很差，五年存活率不到5%。了解PDAC侵袭性和化疗耐药性的分子机制将为新的分子靶向治疗提供基础。为此，我们在这里首次展示了转化生长因子之间存在着动态相互作用。以及STAT3活性，它们有助于PDAC的侵袭性，靶向这些途径可能会阻止侵袭并增强对化疗的敏感性。肿瘤进展的标志之一是转化生长因子的开关？从肿瘤抑制到肿瘤促进的信号传递。转化生长因子看似自相矛盾的这一方面？信号正在接受广泛的调查。转化生长因子？信号通过Smad依赖和Smad非依赖两种途径。我们的研究表明，转化生长因子？在PDAC中需要SMAD信令。然而，超过一半的PDAC存在Smad4基因的等位基因缺失或失活突变。此外，在具有完整Smad成分的肿瘤细胞中，致癌信号可以减弱Smad信号或改变TGF？有利于肿瘤促进的转录反应。我们发现，STAT3在PDAC中被结构性激活，并且Smads和STAT3通路之间存在相互的负调控。在Smad4完整细胞中，敲除STAT3可增强Smad信号转导，抑制转化生长因子？介导的运动和侵袭。在Smad4缺陷的PDAC细胞中，STAT3的活性与转化生长因子？诱导运动性和侵袭性。我们的初步结果还表明，在用吉西他滨和EGFR-激酶抑制剂治疗的PDAC中，STAT3仍然处于激活状态。阻断TGF？/STAT3轴可阻止肿瘤的侵袭并增强对吉西他滨的敏感性。我们的中心假设是，PDAC中的致癌改变导致了一个异常的TGF？/STAT3轴，该轴在功能上与侵袭性和化疗耐药性有关。我们将通过完成以下目标来检验这一假设。目的1.确定STAT3在调节Smad信号中的作用，并确定这是否影响PDAC的肿瘤进展。目的2.确定STAT3活性与Smad4非依赖性转化生长因子之间的相互作用？信号在肿瘤进展中起作用。目的3.确定靶向转化生长因子？/STAT3轴是否能改善PDAC的治疗。 这些研究的完成将进一步明确转化生长因子与细胞因子之间的分子和功能关系。和STAT3，以及这些相互作用在PDAC的侵袭性和对传统疗法的反应中所起的作用。最终，这些研究的成功结果可能会为新的临床试验提供基础。

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.