Myb, a key driver of pancreatic cancer progression and metastasis

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DESCRIPTION (provided by applicant): Pancreatic cancer is a disease of insidious progression. In most cases, it is either locally advanced or has already metastasized to distant sites at the time of diagnosis. Therefore, there is an urgent need to identify novel molecular targets regulating pancreatic cancer pathogenesis, which could enable the development of novel and effective mechanism-based treatment strategies. This proposal is based on our novel findings on a proto-oncogene, Myb, which is amplified in a sub-set of pancreatic cancer. Myb encodes for a transcription factor and confers its oncogenic activity by regulating the expression of a wide array of target genes. Our preliminary findings demonstrate, for the first time, Myb-regulated phenotypic changes in pancreatic cancer. Myb promotes pancreatic cancer cell growth, clonogenicity, migration and invasion. Interestingly, we observe that pancreatic cancer cells undergo a reversal of epithelial to mesenchymal transition (EMT) upon Myb downregulation. Myb-silenced pancreatic cancer cells also exhibit a decreased expression of CXCR4 and c- Myc, two putative target genes of Myb, which have been implicated in pancreatic cancer progression. We also show that Myb is overexpressed in a majority of pancreatic cancer cell lines and tumor tissues. Thus, in this exploratory proposal, we plan to utilize cellular and molecular biological approaches to characterize the role of Myb in pancreatic cancer pathogenesis. Our central hypothesis is that Myb acts as a key player in the pathobiology of pancreatic cancer by regulating the expression of pathogenically relevant gene targets. To address this hypothesis, we propose two specific aims. In specific aim 1, we will investigate the role of Myb in pancreatic cancer pathogenesis using in vitro and in vivo functional assays. We will also examine the role of CXCR4 and c-Myc in potentiating the Myb-induced phenotypic changes and search comprehensively for the additional downstream targets of Myb. In specific aim 2, we will determine the association of Myb expression with disease aggressiveness and survival in pancreatic cancer patients. Here, we will assess the incidence and intensity of aberrant Myb expression in pancreatic cancer and examine any correlation with tumor -grade, - stage, and patient's survival. Having observed a role of Myb in EMT, we will also examine its expression in progressive pre-malignant and malignant lesions to establish a correlation with disease advancement. We will also study a correlation of Myb with CXCR4 and c-Myc expression and determine their collective association with disease aggressiveness and survival of the patients. The knowledge gained from these exploratory studies will greatly enhance our understanding regarding the role and mechanisms of Myb in pancreatic cancer pathogenesis. Furthermore, it will also serve as a foundation to exploit the potential usefulness of Myb as a novel target for diagnosis, prognosis and therapy. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth leading cause of cancer-related mortality in the United States and hence, there is a pressing need to identify novel molecular targets that could lead to the development of more effective diagnostic and treatment strategies. The proposed studies will provide novel information on the pathogenic role of Myb in pancreatic cancer growth and emphasize on its clinical potential in diagnosis, prognosis and therapy. The resulting information, in long term, will be useful for better disease management and thus enhance the life expectancy of patients diagnosed with this devastating and lethal malignancy.