Discovering Spatial Mechanisms Regulating Metastatic Invadopodia in PDAC

在胰腺导管腺癌中主要需要针对kras的新的治疗策略。 (PDAC)，存活率只有5%，令人沮丧。然而，30多年的工作一直未能取得进展 对Kras或其他突变的RAS异构体(HRAs，NRAS)的有效治疗，这解释了 大约30%的人类癌症。我们实验室最近发表的研究表明， 突变激活的Kras利用正前馈机制驱动自身的蛋白质合成，并 独特的平移延伸率eIF5A1。事实上，Kras驱动增加了eIF5A1的表达 反过来，Kras翻译和下游信令的驱动增加，导致细胞增加 扩散和迁徙。最近，我们测试了高度相关的异构体eIF5A2的能力 调节这一途径。令人惊讶的是，我们发现eIF5A2既不调节Kras的表达，也不调节Kras的表达 它能调节PDAC细胞的生长吗？相反，它在调节内侧足的形成方面起着独特的作用 和转移，它独立于eIF5A1运行。EIF5A2介导的身份识别 异搏定的形成和转移是一个重要的突破，因为它提供了一种新的治疗方法 以转移性PDAC为目标的战略，这是迫切需要的。事实上，与eIF5A1不同，eIF5A1普遍存在 EIF5A2在组织中表达，仅限于大脑和睾丸，但在 恶性PDAC组织和转移使其成为理想的生物标志物和治疗靶点。因此， 这项提案中概述的工作将检验eIF5A2调节mRNAs本地化翻译的假设 编码关键转移蛋白，驱动PDAC细胞的侵袭和转移，使用临床相关的， 免疫活性，KCP小鼠PDAC转移模型。拟议的工作很重要，因为 在花盘中调节mrna翻译的机制通常知之甚少，而且 尚未在PDAC进行调查。对这一过程的详细了解可能会揭示新的战略 并以调节eIF5A2蛋白表达、内陷形成和PDAC转移为靶点。是这样的 迫切需要一种方法来开发新的和现有的疗法来对抗这种致命的疾病。 具体目的1.确定5A2在调节5A2、erbB2、PDGFR-b和PEAK1 mRNA中的作用 内脏形成和癌细胞侵袭中的定位、翻译和信号转导。 具体目的2.确定5A2在介导PDAC肿瘤形成和转移中的作用。

There is a major need for new therapeutic strategies that target Kras in pancreatic ductal adenocarcinoma (PDAC) which has a dismal 5% survival rate. However, over 3 decades of work has failed to develop effective therapeutics against Kras or other mutant Ras isoforms (Hras, Nras), which account for approximately 30% of all human cancers. Recent published work in our laboratory revealed that mutationally activated Kras drives its own protein synthesis using a positive feedforward mechanism and the unique translation elongation factors eIF5A1. In fact, Kras drives increased eIF5A1 expression which in turns drives increased in Kras translation and downstream signaling, leading to increased cell proliferation and migration. More recently, we tested the ability of the highly related isoform eIF5A2 to regulate this pathway. Surprisingly, we discovered that eIF5A2 does not regulated Kras expression nor does it regulate PDAC cell growth, but rather it plays a unique role in regulating invadopodia formation and metastasis, which operates independent of eIF5A1. The identification that eIF5A2 mediates invadopodium formation and metastasis is an important breakthrough because it provides a new therapeutic strategy to target metastatic PDAC, which is sorely needed. In fact, unlike eIF5A1, which is ubiquitously expressed in tissues, eIF5A2 expression is restricted to brain and testis, but is selectively upregulated in malignant PDAC tissues and metastases making it an ideal biomarker and therapeutic target. Therefore, work outlined in this proposal will test the hypothesis that eIF5A2 regulates localized translation of mRNAs encoding key metastatic proteins that drive PDAC cell invasion and metastasis using the clinically relevant, immune competent, KCP mouse model of PDAC metastasis. The proposed work is important because the mechanisms that regulate mRNA translation in the invadopodium are poorly understood in general and have not been investigated in PDAC. A detailed understanding of this process could reveal new strategies and targets to modulate eIF5A2 protein expression, invadopodium formation, and PDAC metastasis. Such an approach is sorely needed for development of new and existing therapeutics to fight this deadly disease. Specific Aim 1. To determine the role of 5A2 in mediating 5A2, erbB2, PDGFR-b, and PEAK1 mRNA localization, translation, and signaling in invadopodium formation and cancer cell invasion. Specific Aim 2. To determine the role of 5A2 in mediating PDAC tumor formation and metastasis.