Defining the role of the mitochondrial protein, GOT2, in pancreatic cancer metastasis and epigenetic dysregulation

Project Summary Pancreatic adenocarcinoma (PDAC) is a highly aggressive and deadly form of pancreatic cancer with a poor prognosis and low survival rate. Despite advances in treatment and diagnosis, PDAC is still the third leading cause of cancer-related deaths, often diagnosed at late stages, and resistant to chemotherapy and radiation therapy due to its inherent tumor heterogeneity. The exact cause of PDAC is unknown, but several environmental and genetic risk factors have been identified. Moreover, mutations in genes such as KRAS, TP53, SMAD4, and CDKN2A have been reported as genetic drivers of PDAC progression. In recent studies, epigenetic changes have been shown to play a significant role in the development and progression of PDAC, but the underlying mediators that contribute to these alterations are largely unknown. Previous studies have established a connection between mitochondrial proteins and epigenetic modifications, contributing to the progression of tumorigenesis. Our research team has used mouse orthotopic tumor models to recently report that the mitochondrial protein, GOT2 (glutamic-oxaloacetic transaminase), supports the development of PDAC by exerting an immunosuppressive effect within the tumor microenvironment. Currently, it remains unknown whether GOT2 contributes to the metastasis of PDAC, however, preliminary data seems to suggest that GOT2 may play a role in modifying the epigenetic landscape in mouse PDAC cell line models. To investigate this further, we have meticulously designed our methods to successfully carry out the aims outlined in this proposal, utilizing in vivo mouse tumor models, as well as ChIP- and ATAC-seq experiments in conjunction with bioinformatics approaches. The overall goal of our proposed aims is to gain a better understanding of the mechanisms contributing the epigenetic dysregulation in pancreatic cancer and metastasis. We hypothesize that GOT2 is pro-metastatic and plays a role in reprogramming the epigenetic landscape, which leads to transcriptional profiles that facilitate the metastasis of PDAC. By revealing this new epigenetic role for GOT2, we hope to gain a deeper understanding of the transcriptional and epigenetic programs that enhance the plasticity of tumor cells and drive the progression of PDAC. Ultimately, this will provide new opportunities for the development of more effective treatments to address the increasing medical and societal burdens of pancreatic cancer.