Abstract
Elevated plasma branched-chain amino acid (BCAA) levels are observed in some metabolic disorders, such as obesity and diabetes, due to impaired hepatic BCAA catabolism. In pancreatic cancer, elevated plasma BCAA levels are observed years before diagnosis, possibly due to increased protein degradation. However, the status of BCAA catabolism in pancreatic cancer remains unclear. Here, we hypothesized that defective hepatic BCAA utilization contributes to this elevation in pancreatic cancer, similar to observations in obesity and diabetes. Consistent with our hypothesis, increased phosphorylation of the hepatic BCAA catabolic enzyme, branched-chain α-keto acid dehydrogenase (BCKDH), was observed in a murine nerve invasion model with human pancreatic cancer cells, indicative of an inactive state. Notably, this was associated with reduced whole-body BCAA flux, increased skeletal muscle degradation, and elevated plasma BCAA levels. Patients with stage III pancreatic cancer with severe neural invasion exhibited high plasma BCAA and reduced muscle mass. In addition, patients with stage IV pancreatic cancer showed hepatic BCKDH phosphorylation, which correlated with poor prognosis. Overall, these results suggest the potential existence of impaired BCAA catabolism via hepatic BCKDH downregulation in pancreatic cancer.
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Qualified researchers can contact Shuichi Mitsunaga to request individual-level patient data. The datasets from the animal experiments in the current study are available from Asami Hagiwara upon reasonable request.
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Acknowledgments
We thank Kayo Takei, Miho Akimoto, and Yuriko Sato at the National Cancer Center Hospital East and Michiko Hamamoto at the Exploratory Oncology Research & Clinical Trial Center at the National Cancer Center for their secretarial support; Natsuko Maruyama and Mariko Yajima at the Exploratory Oncology Research & Clinical Trial Center at the National Cancer Center; Toshie Yoshino and Ru Wang in WDB eureka for their support with the experiment; and Miyu Narita at the Tsuruoka Metabolomics Laboratory at the National Cancer Center for her technical assistance. We would like to thank Editage (www.editage.jp) for English language editing. This work was supported in part by research funds from the Yamagata Prefectural Government and City of Tsuruoka.
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This work was supported in part by research funds from the Yamagata Prefectural Government and City of Tsuruoka.
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H **. Michida** : Formal analysis, investigation, methodology, and writing—original draft. **A.H.** : Conceptualization, formal analysis, investigation, methodology, writing—original draft, writing—review & editing, and project administration. **Y.S.** : Investigation, methodology, writing, review & editing. **N.K.** and **M. Kanda** : Formal analysis and investigation. **M. Kawasaki** and **S.K.** : Formal analysis and methodology. **S.S.** : Formal analysis, investigation, writing—original draft and writing—review & editing. **M.I.** : Resources, methodology, writing, review & editing. **H. Makinoshima:** Investigation, methodology, writing—original draft and writing—review & editing. **S.M.** : Conceptualization, formal analysis, investigation, methodology, validation, writing—original draft, writing—review & editing, project administration, and supervision. All authors have read and approved the final version of this manuscript.
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H. Michida, A.H., Y.S., N.K., M. Kanda, M. Kawasaki, and S. K. are employed by Ajinomoto Co. Inc. S.M. reports grants from Ajinomoto, Ono Pharmaceutical, and Pfizer Inc. outside the submitted work; lecture fees from Ono Pharmaceutical, Otsuka Pharmaceutical, and Meiji Seika Pharmaceutical outside the submitted work; and a patent for a biomarker using free plasma amino acids to predict sarcopenia outside the submitted work. M.I. reports grants from Boehringer Ingelheim, Delta-Fly Pharma, N.V., Invitrogen, NIHON SERVIER, and Novartis outside the submitted work; consulting fees from Astellas Pharma, Novartis, and NIHON SERVIER outside the submitted work; and lecture fees from Guardant Health Japan, NIHON SERVIER, Taiho, Nippon Kayaku, and Yakult outside the submitted work. The authors declare no other competing interests.
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Michida, H., Hagiwara, A., Saito, Y. et al. Branched-chain amino acid catabolism is potentially deficient in pancreatic cancer with high-neural invasion. Sci Rep (2026). https://doi.org/10.1038/s41598-026-47741-x
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DOI: https://doi.org/10.1038/s41598-026-47741-x
