Metabolic landscape of clear cell renal cell carcinoma and search for metabolites predictive of drug response
Abstract Background Clear cell renal cell carcinoma (ccRCC) commonly exhibits biallelic inactivation of VHL genes, profoundly impacting intracellular metabolic pathways and utilization of metabolic substrates. The aims of this study were to validate the metabolomic profile previously identified in c...
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BMC
2025-08-01
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| Online Access: | https://doi.org/10.1186/s12885-025-14661-4 |
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| author | Michinobu Ozawa Sei Naito Hideki Makinoshima Hiromi Ito Atsushi Tsuya Takafumi Narisawa Hiroki Fukuhara Yuki Takai Masaki Ushijima Mayu Yagi Hayato Nishida Norihiko Tsuchiya |
| author_facet | Michinobu Ozawa Sei Naito Hideki Makinoshima Hiromi Ito Atsushi Tsuya Takafumi Narisawa Hiroki Fukuhara Yuki Takai Masaki Ushijima Mayu Yagi Hayato Nishida Norihiko Tsuchiya |
| author_sort | Michinobu Ozawa |
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| description | Abstract Background Clear cell renal cell carcinoma (ccRCC) commonly exhibits biallelic inactivation of VHL genes, profoundly impacting intracellular metabolic pathways and utilization of metabolic substrates. The aims of this study were to validate the metabolomic profile previously identified in ccRCC surgical specimens, to construct a metabolic classification in ccRCC, and to exploratorily investigate metabolic biomarkers of systemic therapy response. Materials and methods We first examined the metabolome in 52 paired tumor/normal surgical ccRCC samples, and then compared the metabolites using paired t-test. Unsupervised clustering analysis was done, and the patients were divided into four subgroups. Then tumor grade and transcriptome analyses were compared among the four groups. Finally, to compare the metabolome according to the effect of systemic therapy, we analyzed 9 patients with vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitor (VEGF-TKI) and 11 patients with immune checkpoint blockade (ICB), respectively. Results The upper stream of glycolysis and the pentose phosphate pathway were commonly activated, along with elevated glutamine levels and reduced proteinogenic amino acids (AAs) other than glutamine in ccRCC tissues, consistent with prior findings. Lactate levels, previously reported as elevated, varied across metabolic subgroups. he Metabolic subgroups enriched with high-grade tumors demonstrated lower expression of VEGF pathway-related genes. VEGF-TKI responders showed decreased levels of some fatty acids. ICI responders exhibited reduced levels of tryptophan and hydroquinone. alongside increased levels of pyruvic acid-oxime, 3-hydroxypropinoic acid, and hydroxylamine. Conclusions We validated the landscape of the ccRCC metabolome and identified some metabolites as potential biomarkers for predicting therapeutic response in RCC. |
| format | Article |
| id | doaj-art-d40a60e4429345a79e47184c1e5a55fa |
| institution | Kabale University |
| issn | 1471-2407 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
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| series | BMC Cancer |
| spelling | doaj-art-d40a60e4429345a79e47184c1e5a55fa2025-08-24T11:34:42ZengBMCBMC Cancer1471-24072025-08-0125111110.1186/s12885-025-14661-4Metabolic landscape of clear cell renal cell carcinoma and search for metabolites predictive of drug responseMichinobu Ozawa0Sei Naito1Hideki Makinoshima2Hiromi Ito3Atsushi Tsuya4Takafumi Narisawa5Hiroki Fukuhara6Yuki Takai7Masaki Ushijima8Mayu Yagi9Hayato Nishida10Norihiko Tsuchiya11Department of Urology, Yamagata University Faculty of MedicineDepartment of Urology, Yamagata University Faculty of MedicineTsuruoka Metabolomics Laboratory, National Cancer CenterDepartment of Urology, Yamagata University Faculty of MedicineInstitute for promotion of medical science research, Faculty of Medicine, Yamagata UniversityDepartment of Urology, Yamagata University Faculty of MedicineDepartment of Urology, Yamagata University Faculty of MedicineDepartment of Urology, Yamagata University Faculty of MedicineDepartment of Urology, Yamagata University Faculty of MedicineDepartment of Urology, Yamagata University Faculty of MedicineDepartment of Urology, Yamagata University Faculty of MedicineDepartment of Urology, Yamagata University Faculty of MedicineAbstract Background Clear cell renal cell carcinoma (ccRCC) commonly exhibits biallelic inactivation of VHL genes, profoundly impacting intracellular metabolic pathways and utilization of metabolic substrates. The aims of this study were to validate the metabolomic profile previously identified in ccRCC surgical specimens, to construct a metabolic classification in ccRCC, and to exploratorily investigate metabolic biomarkers of systemic therapy response. Materials and methods We first examined the metabolome in 52 paired tumor/normal surgical ccRCC samples, and then compared the metabolites using paired t-test. Unsupervised clustering analysis was done, and the patients were divided into four subgroups. Then tumor grade and transcriptome analyses were compared among the four groups. Finally, to compare the metabolome according to the effect of systemic therapy, we analyzed 9 patients with vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitor (VEGF-TKI) and 11 patients with immune checkpoint blockade (ICB), respectively. Results The upper stream of glycolysis and the pentose phosphate pathway were commonly activated, along with elevated glutamine levels and reduced proteinogenic amino acids (AAs) other than glutamine in ccRCC tissues, consistent with prior findings. Lactate levels, previously reported as elevated, varied across metabolic subgroups. he Metabolic subgroups enriched with high-grade tumors demonstrated lower expression of VEGF pathway-related genes. VEGF-TKI responders showed decreased levels of some fatty acids. ICI responders exhibited reduced levels of tryptophan and hydroquinone. alongside increased levels of pyruvic acid-oxime, 3-hydroxypropinoic acid, and hydroxylamine. Conclusions We validated the landscape of the ccRCC metabolome and identified some metabolites as potential biomarkers for predicting therapeutic response in RCC.https://doi.org/10.1186/s12885-025-14661-4BiomarkerClear cell renal cell carcinomaKidney cancerMetabolome. |
| spellingShingle | Michinobu Ozawa Sei Naito Hideki Makinoshima Hiromi Ito Atsushi Tsuya Takafumi Narisawa Hiroki Fukuhara Yuki Takai Masaki Ushijima Mayu Yagi Hayato Nishida Norihiko Tsuchiya Metabolic landscape of clear cell renal cell carcinoma and search for metabolites predictive of drug response BMC Cancer Biomarker Clear cell renal cell carcinoma Kidney cancer Metabolome. |
| title | Metabolic landscape of clear cell renal cell carcinoma and search for metabolites predictive of drug response |
| title_full | Metabolic landscape of clear cell renal cell carcinoma and search for metabolites predictive of drug response |
| title_fullStr | Metabolic landscape of clear cell renal cell carcinoma and search for metabolites predictive of drug response |
| title_full_unstemmed | Metabolic landscape of clear cell renal cell carcinoma and search for metabolites predictive of drug response |
| title_short | Metabolic landscape of clear cell renal cell carcinoma and search for metabolites predictive of drug response |
| title_sort | metabolic landscape of clear cell renal cell carcinoma and search for metabolites predictive of drug response |
| topic | Biomarker Clear cell renal cell carcinoma Kidney cancer Metabolome. |
| url | https://doi.org/10.1186/s12885-025-14661-4 |
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