Mechanisms of translational output control in pancreatic cancer

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PROJECT SUMMARY My long-term career goal is to lead a productive academic research group, promoting science by conducting impactful cancer biology research and mentoring the next generation of dedicated scientists. I am particularly interested in the mechanisms of cancer development and resistance to therapy in pancreatic ductal adenocarcinoma (PDAC). PDAC is one of the deadliest disease for which survival has not improved substantially over the past 25 years. There is currently no effective treatment for PDAC patients. The NCI, in accordance to the Recalcitrant Cancer Research Act, established a scientific framework in which the top priorities are the development of targeted therapeutics and therapies to overcome resistance to currently available agents. Our proposed research plan addresses these priorities by identifying poorly recognized non- histone lysine methyltransferase METTL10 as a critical regulator of eEF1A (eukaryotic elongation factor 1 alpha) a fundamental, non-ribosomal component of the mRNA translational machinery. Dysregulation of protein production is a hallmark of cancer and is linked to aberrant cell proliferation, survival, and alterations in both immune responses and cancer energetics. An overarching goal of this K99/R00 proposal focuses on the idea that lysine methylation of eEF1A regulates the rate of protein synthesis, the most energy-consuming process in the cell, and plays a critical role in human cancer growth. The goal of Aim 1 is to elucidate the role of METTL10 in pancreatic cancer driven by oncogenic KRAS. We will test the hypothesis that METTL10, via its methylation activity, cooperates with KRAS signaling to promote the unlimited expansion of cancer cells in vivo using mouse models of pancreas, in which KRAS pathway is frequently activated. We will also investigate the tumorigenic role of METTL10 in human tissue using patient-derived xenograft (PDX) models. Next, we will investigate the role of methylation on specific protein production using ribosome profiling techniques in mouse models of PDAC. Finally, we will explore potential synergies of METTL10 ablation in combination with inhibitors of MAP-kinases in pre-clinical models of pancreatic cancers. In Aim 2 we will characterize the physiologic catalytic activity of the METTL10 and its molecular functions in the regulation of eEF1A activity in vitro and mRNA translation biology in cells. We will also investigate the METTL10 and methylated eEF1A interacting partners and how these pathways intersect to influence cancer cell phenotypes. A K99/R00 training award will allow me to carry out this transformative project, further developing my current skills in mouse genetics, mRNA translation biology, learn new techniques for in vitro and in vivo ribosome profiling analysis while also allowing me to acquire knowledge in clinical aspects of pancreatic cancer and new expertise in biochemical signaling and integrative systems biology.