Discovering Spatial Mechanisms Regulating Metastatic Invadopodia in PDAC

目前迫切需要针对胰腺导管腺癌中Kras的新治疗策略 （PDAC），其存活率为5%。然而，30多年的工作未能发展 针对Kras或其它突变型Ras同种型（Hras、Nras）的有效治疗剂，其导致 大约30%的人类癌症我们实验室最近发表的工作表明， 突变激活的Kras使用正前馈机制驱动其自身的蛋白质合成， 翻译延伸因子eIF5A1。事实上，Kras驱动eIF5A1表达增加， 反过来驱动Kras翻译和下游信号传导的增加，导致细胞增殖的增加。 扩散和迁移。最近，我们测试了高度相关的同种型eIF5A2的能力， 调节这条通路。令人惊讶的是，我们发现eIF5A2不调节Kras表达， 它是否调节PDAC细胞生长，而是在调节侵袭伪足形成中发挥独特作用 和转移，其独立于eIF5A1起作用。eIF5A2介导的鉴定 侵袭足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 针对转移性PDAC的策略，这是非常需要的。事实上，与eIF5A1不同， 在组织中表达，eIF5A2的表达仅限于脑和睾丸，但选择性上调， 恶性PDAC组织和转移使其成为理想的生物标志物和治疗靶标。因此，我们认为， 本计划中概述的工作将检验eIF5A2调节mRNA定位翻译的假设 使用临床相关的， PDAC转移的免疫活性KCP小鼠模型。这项工作之所以重要，是因为 在侵袭足中调节mRNA翻译的机制通常知之甚少， 在PDAC中未进行调查。对这一过程的详细了解可以揭示新的策略 并靶向调节eIF5A2蛋白表达、侵袭足形成和PDAC转移。等 迫切需要一种方法来开发新的和现有的治疗方法来对抗这种致命的疾病。 具体目标1。确定5A2在介导5A2、erbB 2、PDGFR-b和PEAK 1 mRNA中的作用， 在侵袭足形成和癌细胞侵袭中的定位、翻译和信号传导。 具体目标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.