The overall objective of this proposal is to delineate the mechanism of ZIP4-activated ZEB1-dependent metastasis in pancreatic cancer (PC). Investigating the functional impact and the underlying mechanism of this pathway is critical to understand the biology and make inroads on the progression and metastasis of PC. PC has the highest mortality rate of any cancer, with a 5-year survival rate below 8%. Despite progress in improved diagnostic methods and development of targeted therapies, overall survival has not improved significantly over recent decades. It is imperative to understand the biology of PC, and identify novel molecular markers and therapeutic targets in PC in order to develop more effective treatments and reduce drug resistance for this devastating disease. In this proposal, we aim to characterize the molecular mechanisms underlying the function of a key zinc transporter, ZIP4, and a zinc dependent EMT-like transcription factor (EMT-TF) ZEB1 in PC metastasis. Our preliminary data demonstrate that ZIP4 promotes PC growth and metastasis through the modulation of ZEB1. Further studies revealed that this newly identified ZIP4-ZEB1 axis upregulates integrins, and in turn integrin-mediated cell adhesion, migration and invasion. We will use these findings as a foundation to further our understanding of the mechanism(s) underlying ZIP4 oncogenic function in PC. We hypothesize that ZIP4 promotes PC metastasis through a distinct signaling pathway leading to the activation of an EMT-TF ZEB1, and this pathway represents a novel therapeutic target for this dismal disease. Three independent but interrelated specific aims are proposed to address this hypothesis. We will determine the impact of the ZIP4-regulated ZEB1 pathway in PC cells. We will determine the impact of the ZIP4-regulated ZEB1 pathway in two independent mouse models of PC (orthotopic xenograft and spontaneous models). We will also delineate the signaling pathway downstream of ZIP4-activated ZEB1-dependent transcription of integrins in PC. The ZIP4-activated ZEB1 upregulation represents a novel signaling pathway modulating the growth, metastasis, and drug resistance of PC tumors. The proposed studies will help define the mechanism regulating this oncogenic axis and understand the biology of the progression and metastasis of PC. Both mechanistic and functional studies are proposed using state-of-the-art technologies and genetically engineered mouse models. The results obtained from this study will be of high impact since they will significantly advance our understanding on a key zinc transporter and a zinc dependent EMT-TF ZEB1 in PC metastasis.