Thursday, November 21, 2024
11/21/2024
Project Summary Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a poor prognosis and limited treatment options. Multiple lines of evidence have shown that cancer cells frequently become addicted to active nuclear cytoplasmic transport to sustain their activities including growth and metastasis. A RAN gradient, with high nuclear RAN-GTP concentration, is required for proper shuttling between the nucleus and the cytoplasm. The RAN guanine exchange factor, known as regulator of chromosome condensation 1 (RCC1), activates RAN and maintains and catalyzes RAN-GTP formation in the nucleus. The role of this axis in PDAC is not fully understood. Our preliminary data show that high RCC1 is correlated with poor patient prognosis. Our studies demonstrate that Rcc1 depletion in murine PDAC cells alters the steady state distribution of Ran, resulting in widespread alterations in the subcellular proteome. We found that several cellular pathways are impacted by Rcc1 depletion, including amino acid and fatty acid metabolism, as well as RNA processing. Based on these findings, we hypothesize that RCC1 is crucial for PDAC maintenance, and its overexpression may play a role in tumor progression. Therefore, in the F99 phase, I propose to investigate the role and mechanisms by which RCC1 alters PDAC metabolic activity to drive progression using state-of-the-art transcriptomics and metabolomics approaches. I will also delineate the role of the RAN-RCC1 axis in the regulation of mRNA processing and alternative splicing using several imaging and molecular studies. Finally, I will use the well-studied KPC mouse model of PDAC, crossed with a conditional RCC1 overexpression model, to determine the role of RCC1 overexpression in PDAC development and progression. Most patients with PDAC will die due to metastatic disease. In the K00 phase, I will focus on studying the metastatic PDAC process. I will investigate the complex mechanisms of crosstalk between tumor cells and metastasis target organ microenvironment. I aim to determine how the RAN-RCC1 axis is implicated in driving metastatic progression using animal models and patient tissues. Results from these studies aim to improve our understanding of the mechanisms that drive PDAC progression. Our studies will potentially identify potential new vulnerabilities and therapeutic targets with the ultimate goal of improving treatments and outcomes for patients suffering from this aggressive disease.
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