Abstract 6654: Investigating the role of fructose-1,6-bisphosphatase in soft tissue sarcoma

Abstract Glucose metabolism is commonly dysregulated in cancer and other pathological contexts. Fructose-1, 6-bisphosphatase (FBP) is a key rate-limiting gluconeogenic enzyme that converts fructose-1, 6-bisphosphate to fructose-6-phosphate, which produces glucose and glycogen from noncarbohydrate substrates. Two FBP isoforms, FBP1 and FBP2, are differentially expressed in human tissues. FBP1 is expressed in the primary gluconeogenic organs (liver and kidney) to maintain blood glucose levels under fasting conditions. In contrast, FBP2 expression is primarily restricted to striated muscle where it regulates glycogen synthesis. Our recent work demonstrates that both FBP isoforms function as metabolic tumor suppressors and are significantly downregulated in multiple cancers. In sarcoma cells, ectopic FBP2 decreases cytosolic glycolytic flux and FBP2 interacts with nuclear c-Myc to repress transcription of the gene encoding mitochondrial transcription factor A (TFAM), a transcription factor essential for mitochondrial biogenesis. We aim to expand on the roles of FBP2 expression in sarcomas by investigating its binding partners and the role of its catalytic activity in vitro and in vivo. To explore this, we have ectopically expressed wildtype FBP2 and catalytically inactive FBP2-E98A at similar levels to human skeletal muscle in sarcoma cell lines and observed their impacts on proliferation, glucose metabolism, colony formation, invasion, gene expression, and tumor growth. Interestingly, both enzymatically wildtype FBP2 and catalytically inactive FBP2 can suppress proliferation and colony formation in vitro suggesting that FBP2 has additional non-catalytic functions contributing to its repressive role in cancer cells. To explore additional roles of FBP2 outside of its catalytic function, we have developed a FBP2-BioID2 fusion protein and performed immunoprecipitation mass spectrometry to identify novel binding partners of FBP2. Surprisingly, our RNAseq and proteomics data suggest that ectopically expressed wildtype FBP2 may enrich for gene sets and putatively bind with components of the cytoskeleton. Furthermore, to investigate the role of FBP2 loss in sarcomagenesis, we have also utilized autochthonous and injury-induced murine models of undifferentiated pleiomorphic sarcoma with and without Fbp2 loss. We aim to fully characterize these models to elucidate the possible roles of FBP2 in tumor latency, size, and metastasis in sarcoma. Overall, our work will further define the moonlighting roles of FBP2 by elucidating its interactome and the role of FBP2 in coordinating metabolic transitions in sarcomagenesis. Citation Format: Bailey Nance, Brian Keith, Celeste Simon. Investigating the role of fructose-1, 6-bisphosphatase in soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6654.