Abstract LB054: Dual functions of a BCAA aminotransferase in disease progression of human chondrosarcoma

Abstract Chondrosarcoma (CS) is the second most common type of bone cancer. High-grade CS has a poor prognosis, as evidenced by a five-year survival rate of only 7-24% for dedifferentiated CS. This poor outcome is largely due to the limited therapeutic options available, as high-grade CS exhibits significant resistance to chemotherapy and radiotherapy, particularly in relapsed or dedifferentiated types. These challenges underscore the urgent need for developing new therapeutic approaches. Recent studies have identified that branched-chain amino acid (BCAA) metabolism, driven by the BCAA transaminase 1 (BCAT1), is essential for stem cell maintenance and disease progression in a wide range of cancers, including myeloid leukemia and glioma. Elevated BCAT1 expression is associated with poorer prognosis in these malignancies. Here, we examined the functional roles of BCAT1 in CS. Analysis of patient-derived samples demonstrated higher BCAT1 expression in high-grade CS compared with benign enchondroma, suggesting the contribution of BCAT1 to CS progression. Real-time metabolic flow analysis using high-resolution NMR revealed that BCAT1 promotes BCAA production from branched-chain α-keto acids in CS. This finding contrasts with its known role in BCAA degradation in normal cells, indicating altered BCAA metabolism in CS. In a patient-derived xenograft model, BCAT1 knockdown reduced tumor burden, increased chondrocyte differentiation markers, and exhibited an expanded cartilaginous matrix, suggesting that BCAT1 loss induces cell differentiation. Mechanistically, BCAT1 suppresses the expression of chondrocyte differentiation factors by driving 2-hydroxyglutarate production and mediating epigenetic regulation. Furthermore, we uncovered a moonlighting function of BCAT1 in which its cysteine residues scavenge intracellular reactive oxygen species (ROS) independently of transaminase activity. This ROS-scavenging activity contributes to mitotic fidelity in CS cells, thereby sustaining tumor growth. Our data demonstrate for the first time that both enzymatic and non-enzymatic functions of BCAT1 are crucial drivers of CS progression. Targeting BCAT1 may offer a promising therapeutic approach by inducing differentiation and disrupting mitotic maintenance in this aggressive malignancy. Citation Format: Yoshiki Yamamoto, Makoto Nakagawa, John Glushka, Ayaka Maeno, Makoto Tsunoda, Eijiro Shimada, Fumihiko Nakatani, Kazuya Ichihara, Akinobu Matsumoto, Arthur S. Edison, Hironori Kaji, Junya Toguchida, Benjamin A. Alman, Takahiro Ito, Ayuna Hattori. Dual functions of a BCAA aminotransferase in disease progression of human chondrosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB054.