Integrated Signaling in Pancreatic Cancer Progression

 描述（由申请人提供）：侵袭性胰腺癌（PDA）是一种致死性疾病。虽然某些遗传和表观遗传改变多年来已为人们所知，但迄今为止，这尚未产生有用的预防和/或治疗方式。我们的研究目标是确定基因表达的驱动改变，可以用来开发有效的策略来控制PDA的进展。我们以前的研究表明，转录因子FOXM 1在侵袭性PDA中急剧增加，这种失调严重促进PDA生物学，而PanIN没有表现出显著升高的FOXM 1表达。与此形成鲜明对比的是，我们最近的研究表明，与PanIN相比，侵袭性PDA中维生素D受体（VDR）表达的持续缺乏。将VDR丢失与FOXM 1过表达联系起来并从功能上探究其潜在机制对于理解PDA进展至关重要。我们推测VDR表达的下调导致FOXM 1过表达和PDA恶性表型的获得，即，从PanIN转向侵入性PDA。因此，VDR信号传导的激活和/或恢复可以减弱PanIN的进展并使PDA对维生素D治疗敏感。为了验证我们的假设，我们提出了三个具体的目标：（1）确定VDR表达的缺失是否是胰腺癌从PanIN进展到侵袭性PDA的关键事件;（2）确定VDR信号转导失调的关键分子机制及其对PDA进展的机制影响;和（3）确定完整的VDR信号传导是否使PanIN对维生素D治疗敏感，而侵袭性PDA由于VDR表达的丧失而对维生素D不敏感。这三个新的具体目标与临床相关的问题（目标1），机制证实（目标2）和翻译验证 (aim 3），由我们各自的初步数据支持，可以使用我们独特的研究资源进行独立测试，但它们高度相关并相互支持。我们提出的研究将利用MD安德森癌症中心的独特资源，包括我们收集的大量胰腺癌标本和小鼠模型。鉴于我们发现的VDR/FOXM 1的重要作用，我们预测这些研究的完成将为胰腺癌进展的分子基础和分子靶点的鉴定提供有见地的信息，以设计有效的预防和治疗策略;将我们的发现转化为有益的PDA患者是我们的长期目标。 目标.

 DESCRIPTION (provided by applicant): Invasive pancreatic cancer (PDA) is a lethal disease. While certain genetic and epigenetic alterations have been well known for years, to date this has not resulted in useful preventive and/or therapeutic modalities. Our research goal is to identify driving alterations in gene expression that can be utilized to develop effective strategie to control PDA progression. Our previous studies have demonstrated that transcription factor FOXM1 is drastically increased in invasive PDA and this dysregulation critically promotes PDA biology, whereas PanINs do not exhibit substantially elevated FOXM1 expression. In sharp contrast, our recent study has shown a consistent lack of vitamin D receptor (VDR) expression in invasive PDA as compared to that in PanINs. Causally linking VDR loss to FOXM1 overexpression and functionally interrogating the underlying mechanisms are fundamentally important in understanding PDA progression. We postulate that downregulation of VDR expression causes FOXM1 overexpression and consequential acquisition of malignant phenotype in PDA, i.e., a switch from PanINs to invasive PDA. Therefore, activation and/or restoration of VDR signaling could attenuate PanINs progression and sensitize PDA to Vitamin D treatment. To test our hypothesis, we propose three specific aims: (1) Determine whether loss of VDR expression is a critical event of pancreatic cancer progression from PanIN to invasive PDA; (2) Determine the critical molecular mechanisms underlying dysregulation of VDR signaling in and its mechanistic impact on PDA progression; and (3) Determine whether an intact VDR signaling renders PanINs sensitive to Vitamin D treatment, while invasive PDA are refractory to Vitamin D due to loss of VDR expression. These three novel specific aims with clinical relevant question (aim 1), mechanistic substantiation (aim 2) and translational validation (aim 3), are supported by our respective preliminary data and can be tested independently using our unique research resources, yet they are highly interrelated and support one another. Our proposed studies will take advantage of the unique resources available at MD Anderson Cancer Center, including our large collection of pancreatic cancer specimens and mouse models. Given the important role of VDR/FOXM1 we have uncovered, we predict that completion of these studies will provide insightful information for the molecular basis of pancreatic cancer progression and for identification of molecular targets to design effective prevention and treatment strategies; and translation of our findings into benefiting PDA patients is our long term goal.