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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.

在胰管腺癌中，迫切需要新的靶向Kras的治疗策略