Discovering Spatial Mechanisms Regulating Metastatic Invadopodia in PDAC

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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.