Aspartate Transaminases Are Dispensable for Pancreatic Development and Pancreatic Cancer Progression

Abstract Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States. This is due in part to the limited availability of effective treatment options for patients, highlighting a significant need for new targets and approaches. Deregulated metabolism is a hallmark feature of PDA that has gained attention as a promising inroad for therapy. The aspartate transaminases (glutamate oxaloacetate transaminases, cytosolic GOT1 and mitochondrial GOT2) have several important metabolic functions, including maintaining energy and redox balance and generating aspartate, an essential building block in protein and nucleotide biosynthesis. Previous studies of GOT proteins in preclinical tumor transplant models have yielded conflicting results regarding the requirement of GOT1 and GOT2 for PDA tumor growth. To assess the role of GOT proteins in tumor development and tumor maintenance, we generated conditional knockout mice for Got1 and Got2 and crossed these into pancreas-specific models. Whereas loss of either Got does not impact pancreas development, double Got1 and Got2 knockout results in markedly reduced pancreas size and cellularity without overtly impacting endocrine or exocrine function. In genetically engineered cancer models, single Got loss does not impact lesion formation, tumor size, animal survival, or the composition of the tumor microenvironment. Identical results were also observed in orthotopic allograft mouse models. Together, these findings add to a growing body of work illustrating the adaptability of metabolism in cancer. They also emphasize the importance of model selection, the use of multiple independent models, and the in vivo context when studying the role of metabolic programs in cancer. Competing Interest Statement Conflict of Interest: In the past three years, C.A.L. has consulted for Odyssey Therapeutics and Third Rock Ventures, and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-ME1 pathway as a therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015).