Myb, a key driver of pancreatic cancer progression and metastasis

描述（由申请人提供）：胰腺癌是一种隐匿性进展的疾病。在大多数情况下，它要么是局部晚期，要么在诊断时已经转移到远处。因此，迫切需要鉴定调节胰腺癌发病机制的新分子靶点，这可以开发新的和有效的基于机制的治疗策略。这个建议是基于我们对原癌基因Myb的新发现，Myb在胰腺癌的一个子集中被扩增。Myb编码一种转录因子，并通过调节多种靶基因的表达来赋予其致癌活性。我们的初步研究结果首次证实了胰腺癌中Myb调控的表型变化。Myb促进胰腺癌细胞生长、克隆形成、迁移和侵袭。有趣的是，我们观察到胰腺癌细胞在Myb下调后经历上皮向间质转化（EMT）的逆转。Myb沉默的胰腺癌细胞还表现出CXCR 4和c-Myc（Myb的两种推定靶基因）的表达降低，这两种靶基因与胰腺癌进展有关。我们还表明，Myb在大多数胰腺癌细胞系和肿瘤组织中过表达。因此，在这个探索性的建议中，我们计划利用细胞和分子生物学方法来表征Myb在胰腺癌发病机制中的作用。我们的中心假设是Myb通过调节病理相关基因靶点的表达在胰腺癌的病理生物学中起关键作用。为了解决这一假设，我们提出了两个具体目标。在具体目标1中，我们将使用体外和体内功能测定来研究Myb在胰腺癌发病机制中的作用。我们还将研究CXCR 4和c-Myc在增强Myb诱导的表型变化中的作用，并全面寻找Myb的其他下游靶点。在具体目标2中，我们将确定Myb表达与胰腺癌患者的疾病侵袭性和存活率的相关性。在这里，我们将评估胰腺癌中Myb异常表达的发生率和强度，并检查与肿瘤分级、分期和患者生存率的任何相关性。已经观察到Myb在EMT中的作用，我们还将检查其在进行性癌前病变和恶性病变中的表达，以建立与疾病进展的相关性。我们还将研究Myb与CXCR 4和c-Myc表达的相关性，并确定它们与疾病侵袭性和患者生存率的共同关联。从这些探索性研究中获得的知识将大大提高我们对Myb在胰腺癌发病机制中的作用和机制的理解。此外，它也将作为一个潜在的有用的Myb作为一个新的诊断，预后和治疗的目标，开发的基础。 公共卫生相关性： 胰腺癌是美国癌症相关死亡率的第四大原因，因此，迫切需要确定新的分子靶点，以开发更有效的诊断和治疗策略。这些研究将为Myb在胰腺癌生长中的致病作用提供新的信息，并强调其在诊断，预后和治疗中的临床潜力。从长远来看，由此产生的信息将有助于更好地进行疾病管理，从而提高被诊断患有这种毁灭性和致命恶性肿瘤的患者的预期寿命。

DESCRIPTION (provided by applicant): Pancreatic cancer is a disease of insidious progression. In most cases, it is either locally advanced or has already metastasized to distant sites at the time of diagnosis. Therefore, there is an urgent need to identify novel molecular targets regulating pancreatic cancer pathogenesis, which could enable the development of novel and effective mechanism-based treatment strategies. This proposal is based on our novel findings on a proto-oncogene, Myb, which is amplified in a sub-set of pancreatic cancer. Myb encodes for a transcription factor and confers its oncogenic activity by regulating the expression of a wide array of target genes. Our preliminary findings demonstrate, for the first time, Myb-regulated phenotypic changes in pancreatic cancer. Myb promotes pancreatic cancer cell growth, clonogenicity, migration and invasion. Interestingly, we observe that pancreatic cancer cells undergo a reversal of epithelial to mesenchymal transition (EMT) upon Myb downregulation. Myb-silenced pancreatic cancer cells also exhibit a decreased expression of CXCR4 and c- Myc, two putative target genes of Myb, which have been implicated in pancreatic cancer progression. We also show that Myb is overexpressed in a majority of pancreatic cancer cell lines and tumor tissues. Thus, in this exploratory proposal, we plan to utilize cellular and molecular biological approaches to characterize the role of Myb in pancreatic cancer pathogenesis. Our central hypothesis is that Myb acts as a key player in the pathobiology of pancreatic cancer by regulating the expression of pathogenically relevant gene targets. To address this hypothesis, we propose two specific aims. In specific aim 1, we will investigate the role of Myb in pancreatic cancer pathogenesis using in vitro and in vivo functional assays. We will also examine the role of CXCR4 and c-Myc in potentiating the Myb-induced phenotypic changes and search comprehensively for the additional downstream targets of Myb. In specific aim 2, we will determine the association of Myb expression with disease aggressiveness and survival in pancreatic cancer patients. Here, we will assess the incidence and intensity of aberrant Myb expression in pancreatic cancer and examine any correlation with tumor -grade, - stage, and patient's survival. Having observed a role of Myb in EMT, we will also examine its expression in progressive pre-malignant and malignant lesions to establish a correlation with disease advancement. We will also study a correlation of Myb with CXCR4 and c-Myc expression and determine their collective association with disease aggressiveness and survival of the patients. The knowledge gained from these exploratory studies will greatly enhance our understanding regarding the role and mechanisms of Myb in pancreatic cancer pathogenesis. Furthermore, it will also serve as a foundation to exploit the potential usefulness of Myb as a novel target for diagnosis, prognosis and therapy. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth leading cause of cancer-related mortality in the United States and hence, there is a pressing need to identify novel molecular targets that could lead to the development of more effective diagnostic and treatment strategies. The proposed studies will provide novel information on the pathogenic role of Myb in pancreatic cancer growth and emphasize on its clinical potential in diagnosis, prognosis and therapy. The resulting information, in long term, will be useful for better disease management and thus enhance the life expectancy of patients diagnosed with this devastating and lethal malignancy.