Discovering Spatial Mechanisms Regulating Metastatic Invadopodia in PDAC

发现调节 PDAC 转移性侵袭伪足的空间机制

基本信息

批准号：
9973869
负责人：
Richard L. Klemke
金额：
$ 39.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9973869
关键词：
Actins Adenocarcinoma Cell Adhesives Architecture Basement membrane Biochemical Biological Markers Blood Circulation Blood Vessels Brain Capsid Proteins Cell Proliferation Cell Surface Extensions Cell surface Cells Collagen Complex Cues Cytoskeleton DNA Sequence Alteration Development Diagnosis Disease Disseminated Malignant Neoplasm ERBB2 gene Elongation Factor Environment Erythrocytes Extracellular Matrix Extracellular Matrix Proteins F-Actin Fingerprint Genetic Transcription Genetic Translation Human Immunocompetent In Vitro Incidence Investigation Label Laboratories Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Manuals Mediating Membrane Messenger RNA Methods Mutation Neoplasm Metastasis Oncogenic Outpatients Pancreatic Ductal Adenocarcinoma Pathway interactions Patient-Focused Outcomes Peptide Initiation Factors Phosphotransferases Platelet-Derived Growth Factor beta Receptor Play Process Protein Biosynthesis Protein Isoforms Protein Tyrosine Kinase Proteins Proteomics Pseudopodia Publishing RNA Role Route Shapes Signal Transduction Stains Stromal Invasion Structure Surface Survival Rate Tail Technology Testing Testis Therapeutic Therapeutic Agents Time Tissues Translating Translations Treatment Efficacy War Work base cancer cell cell growth cell motility cell transformation clinically relevant confocal imaging druggable target extracellular fighting human disease innovation mouse model mutant novel novel therapeutic intervention pre-clinical protein expression therapeutic target tumor

项目摘要

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.

迫切需要针对胰腺导管腺癌中 Kras 的新治疗策略 (PDAC) 的存活率仅为 5%。然而，3年多的工作却未能取得进展针对 Kras 或其他突变型 Ras 亚型（Hras、Nras）的有效疗法，其中约占所有人类癌症的 30%。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自身的蛋白质合成，独特的翻译延伸因子 eIF5A1。事实上，Kras 驱动 eIF5A1 表达增加，从而反过来又驱动 Kras 翻译和下游信号传导的增加，导致细胞数量增加扩散和迁移。最近，我们测试了高度相关的异构体 eIF5A2 的能力调节该通路。令人惊讶的是，我们发现 eIF5A2 既不调节 Kras 表达，也不调节 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，其运作独立于 eIF5A1。 eIF5A2介导的识别侵袭伪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迫切需要针对转移性 PDAC 的策略。事实上，与无处不在的 eIF5A1 不同 eIF5A2 在组织中表达，其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。所以，该提案中概述的工作将测试 eIF5A2 调节 mRNA 局部翻译的假设使用临床相关的、编码驱动 PDAC 细胞侵袭和转移的关键转移蛋白，具有免疫能力的 PDAC 转移 KCP 小鼠模型。拟议的工作很重要，因为人们对入侵伪足中调节 mRNA 翻译的机制了解甚少，尚未在 PDAC 中进行研究。详细了解这一过程可以揭示新的策略并以调节 eIF5A2 蛋白表达、侵袭伪足形成和 PDAC 转移为目标。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。具体目标 1. 确定 5A2 在介导 5A2、erbB2、PDGFR-b 和 PEAK1 mRNA 中的作用侵袭伪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。