Details of a Researcher - Soga, Tomoyoshi

Papers - Soga, Tomoyoshi

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Time and dose selective glucose metabolism for glucose homeostasis and energy conversion in the liver

Pan, Y., Hatano, A., Ohno, S., Morita, K., Kokaji, T., Bai, Y., Sugimoto, H., Egami, R., Terakawa, A., Li, D., Uematsu, S., Maehara, H., Fujita, S., Inoue, H., Inaba, Y., Nagano, A., Hirayama, A., Soga, T., Kuroda, S.

npj Syst. Biol. Appl. 10 ( 1 ) 107 - 107 2024.09

Research paper (scientific journal), Joint Work, Accepted

Hepatic glucose metabolism serves dual purposes: maintaining glucose homeostasis and converting glucose into energy sources; however, the underlying mechanisms are unclear. We quantitatively measured liver metabolites, gene expression, and phosphorylated insulin signaling molecules in mice orally administered varying doses of glucose, and constructed a transomic network. Rapid phosphorylation of insulin signaling molecules in response to glucose intake was observed, in contrast to the more gradual changes in gene expression. Glycolytic and gluconeogenic metabolites and expression of genes involved in glucose metabolism including glucose-6-phosphate, G6pc, and Pck1, demonstrated high glucose dose sensitivity. Whereas, glucokinase expression and glycogen accumulation showed low glucose dose sensitivity. During the early phase after glucose intake, metabolic flux was geared towards glucose homeostasis regardless of the glucose dose but shifted towards energy conversion during the late phase at higher glucose doses. Our research provides a comprehensive view of time- and dose-dependent selective glucose metabolism.

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A Supramolecular Biosensor for Rapid and High-ThroughputQuantification of a Disease-Associated Niacin Metabolite

Ueno, M., Sugiyama, H., Li, F., Nishimura, T., Arakawa, H., Chen, X., Cheng, X., Takeuchi,, S., Takeshita, Y., Takamura, T., Miyagi, S., Toyama, T., Soga, T., Masuo, Y., Kato, Y., Nakamura, H., Tsujiguchi, H., Hara, A., Tajima, A., Noguchi-Shinohara, M., Ono, K., Kurayoshi, K., Kobayashi, M., Tadokoro, Y., Kasahara, A., Shoulkamy, M.I., Maeda, K., Ogoshi, T., Hirao, A.

Anal. Chem. 96 ( 36 ) 14499 - 14507 2024.09

Research paper (scientific journal), Joint Work, Accepted

Metabolic abnormalities play a pivotal role in various pathological conditions, necessitating the quantification of specific metabolites for diagnosis. While mass spectrometry remains the primary method for metabolite measurement, its limited throughput underscores the need for biosensors capable of rapid detection. Previously, we reported that pillar[6]arene with 12 carboxylate groups (P6AC) forms host-guest complexes with 1-methylnicotinamide (1-MNA), which is produced in vivo by nicotinamide N-methyltransferase (NNMT). P6AC acts as a biosensor by measuring the fluorescence quenching caused by photoinduced electron transfer upon 1-MNA binding. However, the low sensitivity of P6AC makes it impractical for detecting 1-MNA in unpurified biological samples. In this study, we found that P6A with 12 sulfonate groups (P6AS) is a specific and potent supramolecular host for 1-MNA interactions even in biological samples. The 1-MNA binding affinity of P6AS in water was found to be (5.68 ± 1.02) × 106 M-1, which is approximately 700-fold higher than that of P6AC. Moreover, the 1-MNA detection limit of P6AS was determined to be 2.84 × 10-7 M, which is substantially lower than that of P6AC. Direct addition of P6AS to culture medium was sufficient to quantify 1-MNA produced by cancer cells. Furthermore, this sensor was able to specifically detect 1-MNA even in unpurified human urine. P6AS therefore enables rapid and high-throughput quantification of 1-MNA, and further improvement of our strategy will contribute to the establishment of high-throughput screening of NNMT inhibitors, diagnosis of liver diseases, and imaging of human cancer cells in vivo.

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Metabolomics Profiles Alterations in Cigarette Smokers and Heated Tobacco Product Users

Harada, S., Ohmomo, H., Matsumoto, M., Sata, M., Iida, M., Hirata, A., Miyagawa, N., Kuwabara, K., Kato, S., Toki, R., Edagawa, S., Sugiyama, D., Sato, A., Hirayama, A., Sugimoto, M., Soga, T., Tomita, M., Shimizu, A., Okamura, T., Takebayashi, T.

J. Epidemiol. 34 ( 9 ) 403 - 410 2024.09

Research paper (scientific journal), Joint Work, Accepted

Background: Heated tobacco products (HTPs) have gained global popularity, but their health risks remain unclear. Therefore, the current study aimed to identify plasma metabolites associated with smoking and HTP use in a large Japanese population to improve health risk assessment.

Methods: Metabolomics data from 9,922 baseline participants of the Tsuruoka Metabolomics Cohort Study (TMCS) were analyzed to determine the association between smoking habits and plasma metabolites. Moreover, alterations in smoking-related metabolites among HTP users were examined based on data obtained from 3,334 participants involved from April 2018 to June 2019 in a follow-up survey.

Results: Our study revealed that cigarette smokers had metabolomics profiles distinct from never smokers, with 22 polar metabolites identified as candidate biomarkers for smoking. These biomarker profiles of HTP users were closer to those of cigarette smokers than those of never smokers. The concentration of glutamate was higher in cigarette smokers, and biomarkers involved in glutamate metabolism were also associated with cigarette smoking and HTP use. Network pathway analysis showed that smoking was associated with the glutamate pathway, which could lead to endothelial dysfunction and atherosclerosis of the vessels.

Conclusions: Our study showed that the glutamate pathway is affected by habitual smoking. These changes in the glutamate pathway may partly explain the mechanism by which cigarette smoking causes cardiovascular disease. HTP use was also associated with glutamate metabolism, indicating that HTP use may contribute to the development of cardiovascular disease through mechanisms similar to those in cigarette use.

Keywords: electronic nicotine delivery devices; heated tobacco products; metabolomics; prevention; smoking-induced disease.

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The role of cytidine 5'-triphosphate synthetase 1 in metabolic rewiring during epithelial-to-mesenchymal transition in non-small-cell lung cancer

Nakasuka, F., Hirayama, A., Mkinoshima, H., Yano, S., Soga, T., Tabata, S.

FEBS Open Bio 14 ( 9 ) 1570 - 1583 2024.09

Research paper (scientific journal), Joint Work, Accepted

Epithelial-to-mesenchymal transition (EMT) contributes to the poor prognosis of patients with cancer by promoting distant metastasis and anti-cancer drug resistance. Several distinct metabolic alterations have been identified as key EMT phenotypes. In the present study, we further characterize the role of transforming growth factor-β (TGF-β)-induced EMT in non-small-cell lung cancer. Our study revealed that TGF-β plays a role in EMT functions by upregulation of cytidine 5'-triphosphate synthetase 1 (CTPS), a vital enzyme for CTP biosynthesis in the pyrimidine metabolic pathway. Both knockdown and enzymatic inhibition of CTPS reduced TGF-β-induced changes in EMT marker expression, chemoresistance and migration in vitro. Moreover, CTPS knockdown counteracted the TGF-β-mediated downregulation of UDP-glucuronate, glutarate, creatine, taurine and nicotinamide. These findings indicate that CTPS plays a multifaceted role in EMT metabolism, which is crucial for the malignant transformation of cancer through EMT, and underline its potential as a promising therapeutic target for preventing drug resistance and metastasis in non-small-cell lung cancer.

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Gut microbial factors predict disease severity in a mouse model of multiple sclerosis

Steimle, A., Neumann, M., Grant, E.T., Willieme, S., Sciscio, A.D., Parrish, A., Ollert, M., Miyauchi, E., Soga, T., Fukuda, S., Ohno, H., Desai, M.S.

Nat. Microbiol. 9 ( 9 ) 2244 - 2261 2024.09

Research paper (scientific journal), Joint Work, Accepted

Gut bacteria are linked to neurodegenerative diseases but the risk factors beyond microbiota composition are limited. Here we used a pre-clinical model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), to identify microbial risk factors. Mice with different genotypes and complex microbiotas or six combinations of a synthetic human microbiota were analysed, resulting in varying probabilities of severe neuroinflammation. However, the presence or relative abundances of suspected microbial risk factors failed to predict disease severity. Akkermansia muciniphila, often associated with MS, exhibited variable associations with EAE severity depending on the background microbiota. Significant inter-individual disease course variations were observed among mice harbouring the same microbiota. Evaluation of microbial functional characteristics and host immune responses demonstrated that the immunoglobulin A coating index of certain bacteria before disease onset is a robust individualized predictor of disease development. Our study highlights the need to consider microbial community networks and host-specific bidirectional interactions when aiming to predict severity of neuroinflammation.

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FDX2, an iron-sulfur cluster assembly factor, is essential to prevent cellular senescence, apoptosis or ferroptosis of ovarian cancer cells

Miyahara, S., Ohuchi, M., Nomura, M., Hashimoto, E., Soga, T., Saito, R., Hayashi, K., Sato, T., Saito, M., Yamashita, Y., Shimada, M., Yaegashi, N., Yamada, H., Tanuma, N.

J. Biol. Chem. 300 ( 9 ) 107678 - 107678 2024.09

Research paper (scientific journal), Accepted

Recent studies reveal that biosynthesis of iron-sulfur clusters (Fe-Ss) is essential for cell proliferation, including that of cancer cells. Nonetheless, it remains unclear how Fe-S biosynthesis functions in cell proliferation/survival. Here, we report that proper Fe-S biosynthesis is essential to prevent cellular senescence, apoptosis, or ferroptosis, depending on cell context. To assess these outcomes in cancer, we developed an ovarian cancer line with conditional KO of FDX2, a component of the core Fe-S assembly complex. FDX2 loss induced global downregulation of Fe-S-containing proteins and Fe2+ overload, resulting in DNA damage and p53 pathway activation, and driving the senescence program. p53 deficiency augmented DNA damage responses upon FDX2 loss, resulting in apoptosis rather than senescence. FDX2 loss also sensitized cells to ferroptosis, as evidenced by compromised redox homeostasis of membrane phospholipids. Our results suggest that p53 status and phospholipid homeostatic activity are critical determinants of diverse biological outcomes of Fe-S deficiency in cancer cells.

Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS)

Harada, S., Iida, M., Miyagawa, N., Hirata, A., Kuwabara, K., Matsumoto, M., Okamura, T., Edagawa, S., Kawada, Y., Miyake, A., Toki , R., Akiyama, M., Kawai, A., Sugiyama, D., Sato, Y., Takemura, R., Fukai, K., Ishibashi, Y., Kato, S., Kurihara, A., Sata, M., Shibuki, T., Takeuchi, A., Kohsaka, S., Sawano, M., Shoji, S., Izawa, Y., Katsumata, M., Oki, K., Takahashi, S., Takizawa, T., Maruya, H., Nishiwaki, Y., Kawasaki, R., Hirayama, A., Ishikawa, T., Saito, R., Sato, A., Soga, T., Sugimoto, M., Tomita, M., Komaki, S., Ohmomo, H., Ono, K., Otsuka-Yamasaki, Y., Shimizu, A., Sutoh, Y., Hozawa, A., Kinoshita, K., Koshiba, S., Kumada, K., Ogishima, S., Sakurai-Yageta, M., Tamiya, G., Takebayashi, T.

J. Epidemiol. 34 ( 8 ) 393 - 401 2024.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 09175040

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

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Dynamics of the gut microbiome in FAP patients undergoing intensive endoscopic reduction of polyp burden

Mizutani, S., Tamaki, A., Shiba, S., Salim, F., Yamada, M., Takamaru, H., Nakajima, T., Yoshida, N., Ikuta, S., Yachida, T., Shibata, T., Soga, T., Saito, Y., Fukuda, S., Ishikawa, H., Yamada, T., Yachida, S.

Gut online 2024.08

Joint Work, Accepted

Prognostic Significance of 18F-FDG PET/CT and Tumor Metabolic Changes in Patients With Pancreatic Ductal Adenocarcinoma

Shimomura, A., Oshima, M., Suto, H., Matsukawa, H., Kondo, A., Ando, Y., Kishino, T., Kumamoto, K., Sato, K., Sugimoto, M., Nagao, M., Miyatake, N., Norikane, T., Soga, T., Okano, K.

Anticancer Res. 44 ( 8 ) 3321 - 3330 2024.08

Research paper (scientific journal), Joint Work, Accepted

Background/aim: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is reportedly associated with the malignant potential of cancer. This study aimed to evaluate the association between FDG accumulation and tumor metabolism in pancreatic ductal adenocarcinoma (PDAC).

Patients and methods: A prognostic analysis of data from 131 patients with PDAC who underwent FDG-PET/CT before curative-intent pancreatic surgery was performed. Capillary electrophoresis-mass spectrometry (CE-MS) was used to analyze the metabolome of tumor and non-neoplastic pancreas from 80 patients. These patients were divided into two groups: low SUVmax group (SUVmax <6.09) and high SUVmax group (SUVmax ≥6.09).

Results: Carbohydrate antigen 19-9 (CA19-9), maximum standardized uptake value (SUVmax) of PET, N stage, and postoperative chemotherapy were identified as significant prognostic factors by univariate analysis. SUVmax emerged as an independent prognostic factor for overall survival [hazard ratio (HR)=1.88, p<0.05] and disease-free survival (HR=2.01, p<0.05) in multivariate analysis. Metabolic analyses confirmed that 43 metabolites significantly differed depending on the accumulation of SUV in tumors. Metabolites involved in the removal of reactive oxygen species (e.g., hypotaurine, glutathione, Met), treatment resistance (UDP-N-acetylglucosamine), and proliferation (e.g., choline, leucine, isoleucine) were increased in the high SUVmax group.

Conclusion: FDG accumulation is an important independent prognostic factor reflecting tumor activity associated with metabolic changes in cancer cells.

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Fusobacterium species are distinctly associated with patients with Lynch Syndrome colorectal cancer

Salim, F., Mizutani, S., Shiba, S., Takamaru, H., Yamada, M., Nakajima, T., Yachida, T., Soga, T., Saito, Y., Fukuda, S., Yachida, S., Yamada, T.

iScience 27 ( 7 ) 110181 - 110181 2024.07

Research paper (scientific journal), Joint Work, Accepted

Accumulating evidence demonstrates clear correlation between the gut microbiota and sporadic colorectal cancer (CRC). Despite this, there is limited understanding of the association between the gut microbiota and CRC in Lynch Syndrome (LS), a hereditary type of CRC. Here, we analyzed fecal shotgun metagenomic and targeted metabolomic of 71 Japanese LS subjects. A previously published Japanese sporadic CRC cohort, which includes non-LS controls, was utilized as a non-LS cohort (n = 437). LS subjects exhibited reduced microbial diversity and low-Faecalibacterium enterotypes compared to non-LS. Patients with LS-CRC had higher levels of Fusobacterium nucleatum and fap2. Differential fecal metabolites and functional genes suggest heightened degradation of lysine and arginine in LS-CRC. A comparison between LS and non-LS subjects prior to adenoma formation revealed distinct fecal metabolites of LS subjects. These findings suggest that the gut microbiota plays a more responsive role in CRC tumorigenesis in patients with LS than those without LS.

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Association of Nonalcoholic Fatty Liver Disease with Arterial Stiffness and its Metabolomic Profiling in Japanese Community-Dwellers

Hirata, A., Harada, S., Iida, M., Kurihara, A., Fukai, K., Kuwabara, K., Kato, S., Matsumoto, M., Sata, M., Miyagawa, N., Toki, R., Edagawa, S., Sugiyama, D., Sato, A., Hirayama, A., Sugimoto, M., Soga, T., Tomita, M., Okamura, T., Takebayashi, T.

J. Atheroscler. Thromb. 31 ( 7 ) 1031 - 1047 2024.07

Research paper (scientific journal), Joint Work, Accepted

Aims: Nonalcoholic fatty liver disease (NAFLD) is known to be associated with atherosclerosis. This study focused on upstream changes in the process by which NAFLD leads to atherosclerosis. The study aimed to confirm the association between NAFLD and the cardio-ankle vascular index (CAVI), an indicator of subclinical atherosclerosis, and explore metabolites involved in both by assessing 94 plasma polar metabolites.

Methods: A total of 928 Japanese community-dwellers (306 men and 622 women) were included in this study. The association between NAFLD and CAVI was examined using a multivariable regression model adjusted for confounders. Metabolites commonly associated with NAFLD and CAVI were investigated using linear mixed-effects models in which batch numbers of metabolite measurements were used as a random-effects variable, and false discovery rate-adjusted p-values were calculated. To determine the extent to which these metabolites mediated the association between NAFLD and CAVI, mediation analysis was conducted.

Results: NAFLD was positively associated with CAVI (coefficients [95% Confidence intervals (CI)]=0.23 [0.09-0.37]; p=0.001). A total of 10 metabolites were involved in NAFLD and CAVI, namely, branched-chain amino acids (BCAAs; valine, leucine, and isoleucine), aromatic amino acids (AAAs; tyrosine and tryptophan), alanine, proline, glutamic acid, glycerophosphorylcholine, and 4-methyl-2-oxopentanoate. Mediation analysis showed that BCAAs mediated more than 20% of the total effect in the association between NAFLD and CAVI.

Conclusions: NAFLD was associated with a marker of atherosclerosis, and several metabolites related to insulin resistance, including BCAAs and AAAs, could be involved in the process by which NAFLD leads to atherosclerosis.

Keywords: Atherosclerosis; Branched-chain amino acids; Cardio-ankle vascular index; Insulin resistance; Metabolites; Nonalcoholic fatty liver disease.

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SGLT2 inhibition eliminates senescent cells and alleviates pathological aging

Katsuumi, G., Shimizu, I., Suda, M., Yoshida, Y., Furihata, T., Joki, Y., Hsiao, CL., Jiaqi, L., Fujiki, S., Abe, M., Sugimoto, M., Soga, T., Minamino, T

Nat. Aging 4 ( 7 ) 926 - 938 2024.07

Research paper (scientific journal), Joint Work, Accepted

It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium-glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.

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The γ-glutamyl cycle serves as an amino acids supply system in colorectal cancer organoids under chronic hypoxia

Tabata, S., Endo, H., Makinoshima, H., Soga, T., Inoue, M.

Biochem. Biophys. Res. Commun. (Biochemical and Biophysical Research Communications) 714 149977 - 149977 2024.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 0006291X

Malignant tumors are characterized by a hypoxic microenvironment, and metabolic reprogramming is necessary to ensure energy production and oxidative stress resistance. Although the microenvironmental properties of tumors vary under acute and chronic hypoxia, studies on chronic hypoxia-induced metabolic changes are limited. In the present study, we performed a comprehensive metabolic analysis in a chronic hypoxia model using colorectal cancer (CRC) organoids, and identified an amino acid supply system through the γ-glutamyl cycle, a glutathione recycling pathway. We analyzed the metabolic changes caused by hypoxia over time and observed that chronic hypoxia resulted in an increase in 5-oxoproline and a decrease in oxidized glutathione (GSSG) compared to acute hypoxia. These findings suggest that chronic hypoxia induces metabolic changes in the γ-glutamyl cycle. Moreover, inhibition of the γ-glutamyl cycle via γ-glutamyl cyclotransferase (GGCT) and γ-glutamyl transferase 1 (GGT1) knockdown significantly reversed chronic hypoxia-induced upregulation of 5-oxoproline and several amino acids. Notably, GGT1 knockdown downregulated the intracellular levels of γ-glutamyl amino acids. Conclusively, these results indicate that the γ-glutamyl cycle serves as an amino acid supply system in CRC under chronic hypoxia, which provides fresh insight into cancer metabolism under chronic hypoxia.

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Molecular subtypes of lung adenocarcinoma present distinct immune tumor microenvironments

Fukuda, H., Arai, K., Mizuno, H., Nishito, Y., Motoi, N., Arai, Y., Hiraoka, N., Shibata, T., Sonobe, Y., Kayukawa, Y., Hashimoto, E., Takahashi, M., Fujii, E., Maruyama, T., Kuwabara, K., Nishizawa, T., Mizoguchi, Y., Yoshida, Y., Watanabe, S., Yamashita, M., Kitano, S., Sakamoto, H., Nagata, Y., Mitsumori, R., Ozaki, K., Niida, S., Kanai, Y., Hirayama, A., Soga, T., Tsukada, K., Yabuki, N., Shimada, M., Kitazawa, T., Natori, O., Sawada, N., Kato, A., Yoshida, T., Yasuda, K., Ochiai, A., Tsunoda, H., Aoki, K

Cancer Sci. (Cancer Science) 115 ( 6 ) 1763 - 1777 2024.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 13479032

Overcoming resistance to immune checkpoint inhibitors is an important issue in patients with non-small-cell lung cancer (NSCLC). Transcriptome analysis shows that adenocarcinoma can be divided into three molecular subtypes: terminal respiratory unit (TRU), proximal proliferative (PP), and proximal inflammatory (PI), and squamous cell carcinoma (LUSQ) into four. However, the immunological characteristics of these subtypes are not fully understood. In this study, we investigated the immune landscape of NSCLC tissues in molecular subtypes using a multi-omics dataset, including tumor-infiltrating leukocytes (TILs) analyzed using flow cytometry, RNA sequences, whole exome sequences, metabolomic analysis, and clinicopathologic findings. In the PI subtype, the number of TILs increased and the immune response in the tumor microenvironment (TME) was activated, as indicated by high levels of tertiary lymphoid structures, and high cytotoxic marker levels. Patient prognosis was worse in the PP subtype than in other adenocarcinoma subtypes. Glucose transporter 1 (GLUT1) expression levels were upregulated and lactate accumulated in the TME of the PP subtype. This could lead to the formation of an immunosuppressive TME, including the inactivation of antigen-presenting cells. The TRU subtype had low biological malignancy and "cold" tumor-immune phenotypes. Squamous cell carcinoma (LUSQ) did not show distinct immunological characteristics in its respective subtypes. Elucidation of the immune characteristics of molecular subtypes could lead to the development of personalized immune therapy for lung cancer. Immune checkpoint inhibitors could be an effective treatment for the PI subtype. Glycolysis is a potential target for converting an immunosuppressive TME into an antitumorigenic TME in the PP subtype.

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Serum Carbohydrate Antigen 19-9 and Metabolite Hypotaurine Are Predictive Markers for Early Recurrence of Pancreatic Ductal Adenocarcinoma

Nagao, M., Oshima, M., Suto, H., Sugimoto, M., Enomoto, A., Murakami, T., Shimomura, A., Wada, Y., Matsukawa, H., Ando, Y., Kishino, T., Kumamoto, K., Kobara, H., Kamada, H., Masaki, T., Soga, T., Okano, K.

Pancreas (Pancreas) 53 ( 4 ) e301 - e309 2024.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 08853177

Objective: A significant number of patients experience early recurrence after surgical resection for pancreatic ductal adenocarcinoma (PDAC), negating the benefit of surgery. The present study conducted clinicopathologic and metabolomic analyses to explore the factors associated with the early recurrence of PDAC.

Materials and methods: Patients who underwent pancreatectomy for PDAC at Kagawa University Hospital between 2011 and 2020 were enrolled. Tissue samples of PDAC and nonneoplastic pancreas were collected and frozen immediately after resection. Charged metabolites were quantified by capillary electrophoresis-mass spectrometry. Patients who relapsed within 1 year were defined as the early recurrence group.

Results: Frozen tumor tissue and nonneoplastic pancreas were collected from 79 patients. The clinicopathologic analysis identified 11 predictive factors, including preoperative carbohydrate antigen 19-9 levels. The metabolomic analysis revealed that only hypotaurine was a significant risk factor for early recurrence. A multivariate analysis, including clinical and metabolic factors, showed that carbohydrate antigen 19-9 and hypotaurine were independent risk factors for early recurrence (P = 0.045 and P = 0.049, respectively). The recurrence-free survival rate 1 year after surgery with both risk factors was only 25%.

Conclusions: Our results suggested that tumor hypotaurine is a potential metabolite associated with early recurrence. Carbohydrate antigen 19-9 and hypotaurine showed a vital utility for predicting early recurrence.

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A population-based urinary and plasma metabolomics study of environmental exposure to cadmium

Ishibashi, Y., Harada, S., Eitaki, Y., Kurihara, A., Kato, S., Kuwabara, K., Iida, M., Hirata, A., Sata, M., Matsumoto, M., Shibuki, T., Okamura, T., Sugiyama, D., Sato, A., Amano, K., Hirayama, A., Sugimoto, M., Soga, T., Tomita, M., Takebayashi, T.

Environ. Health Prev. (Med.) 29 22 2024.03

Research paper (scientific journal), Joint Work

Background: The application of metabolomics-based profiles in environmental epidemiological studies is a promising approach to refine the process of health risk assessment. We aimed to identify potential metabolomics-based profiles in urine and plasma for the detection of relatively low-level cadmium (Cd) exposure in large population-based studies.

Method: We analyzed 123 urinary metabolites and 94 plasma metabolites detected in fasting urine and plasma samples collected from 1,412 men and 2,022 women involved in the Tsuruoka Metabolomics Cohort Study. Regression analysis was performed for urinary N-acetyl-beta-D-glucosaminidase (NAG), plasma, and urinary metabolites as dependent variables, and urinary Cd (U-Cd, quartile) as an independent variable. The multivariable regression model included age, gender, systolic blood pressure, smoking, rice intake, BMI, glycated hemoglobin, low-density lipoprotein cholesterol, alcohol consumption, physical activity, educational history, dietary energy intake, urinary Na/K ratio, and uric acid. Pathway-network analysis was carried out to visualize the metabolite networks linked to Cd exposure.

Result: Urinary NAG was positively associated with U-Cd, but not at lower concentrations (Q2). Among urinary metabolites in the total population, 45 metabolites showed associations with U-Cd in the unadjusted and adjusted models after adjusting for the multiplicity of comparison with FDR. There were 12 urinary metabolites which showed consistent associations between Cd exposure from Q2 to Q4. Among plasma metabolites, six cations and one anion were positively associated with U-Cd, whereas alanine, creatinine, and isoleucine were negatively associated with U-Cd. Our results were robust by statistical adjustment of various confounders. Pathway-network analysis revealed metabolites and upstream regulator changes associated with mitochondria (ACACB, UCP2, and metabolites related to the TCA cycle).

Conclusion: These results suggested that U-Cd was associated with metabolites related to upstream mitochondrial dysfunction in a dose-dependent manner. Our data will help develop environmental Cd exposure profiles for human populations.

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Trans-omic analysis reveals opposite metabolic dysregulation between feeding and fasting in liver associated with obesity

10. Bai, Y., Morita, K., Kokaji, T., Hatano, A., Ohno, S., Egami, R., Pan, Y., Li, D., Yugi, K., Uematsu, S., Inoue, H., Inaba, Y., Suzuki, Y., Matsumoto, M., Takahashi, M., Izumi, Y., Bamba, T., Hirayama, A., Soga, T., Kuroda, S.

iScience 27 ( 3 ) 109121 - 109121 2024.03

Research paper (scientific journal), Joint Work, Accepted

Dysregulation of liver metabolism associated with obesity during feeding and fasting leads to the breakdown of metabolic homeostasis. However, the underlying mechanism remains unknown. Here, we measured multi-omics data in the liver of wild-type and leptin-deficient obese (ob/ob) mice at ad libitum feeding and constructed a differential regulatory trans-omic network of metabolic reactions. We compared the trans-omic network at feeding with that at 16 h fasting constructed in our previous study. Intermediate metabolites in glycolytic and nucleotide metabolism decreased in ob/ob mice at feeding but increased at fasting. Allosteric regulation reversely shifted between feeding and fasting, generally showing activation at feeding while inhibition at fasting in ob/ob mice. Transcriptional regulation was similar between feeding and fasting, generally showing inhibiting transcription factor regulations and activating enzyme protein regulations in ob/ob mice. The opposite metabolic dysregulation between feeding and fasting characterizes breakdown of metabolic homeostasis associated with obesity.

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Genetic mutation in Escherichia coli genome during adaptation to the murine intestine is optimized for the host diet

Tsukimi, T., Obana, N., Shigemori, S., Arakawa, K., Miyauchi, E., Yang, J., Song, I., Ashino, Y., Wakayama, M., Soga, T., Tomita, M., Ohno, H., Mori, H., Fukuda, S.

mSystems (mSystems) 9 ( 2 ) e0112323 - e0112323 2024.02

Research paper (scientific journal), Joint Work, Accepted

The gut microbiota is closely associated with human health and is greatly impacted by the host diet. Bacteria such as Escherichia coli live in the gut all throughout the life of a human host and adapt to the intestinal environment. Adaptive mutations in E. coli are reported to enhance fitness in the mammalian intestine, but to what extent is still poorly known. It is also unknown whether the host diet affects what genes are mutated and to what extent fitness is affected. This study suggests that genetic mutations in the E. coli K-12 strain are selected in response to the intestinal environment and facilitate efficient utilization of abundant nutrients in the germ-free mouse intestine. Our study provides a better understanding of these intestinal adaptation mechanisms of gut microbes.

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Reliability of Time-Series Plasma Metabolome Data over 6 Years in a Large-Scale Cohort Study

Miyake, A., Harada, S., Sugiyama, D., Matsumoto, M., Hirata, A., Miyagawa, N., Toki, R., Edagawa, S., Kuwabara, K., Okamura, T., Sato, A., Amano, K., Hirayama, A., Sugimoto, M., Soga, T., Tomita, M., Arakawa, K., Takebayashi, T., Iida, M.

Metabolites (Metabolites) 14 ( 1 ) 77 - 77 2024.01

Research paper (scientific journal), Joint Work, Accepted

Studies examining long-term longitudinal metabolomic data and their reliability in large-scale populations are limited. Therefore, we aimed to evaluate the reliability of repeated measurements of plasma metabolites in a prospective cohort setting and to explore intra-individual concentration changes at three time points over a 6-year period. The study participants included 2999 individuals (1317 men and 1682 women) from the Tsuruoka Metabolomics Cohort Study, who participated in all three surveys-at baseline, 3 years, and 6 years. In each survey, 94 plasma metabolites were quantified for each individual and quality control (QC) sample. The coefficients of variation of QC, intraclass correlation coefficients, and change rates of QC were calculated for each metabolite, and their reliability was classified into three categories: excellent, fair to good, and poor. Seventy-six percent (71/94) of metabolites were classified as fair to good or better. Of the 39 metabolites grouped as excellent, 29 (74%) in men and 26 (67%) in women showed significant intra-individual changes over 6 years. Overall, our study demonstrated a high degree of reliability for repeated metabolome measurements. Many highly reliable metabolites showed significant changes over the 6-year period, suggesting that repeated longitudinal metabolome measurements are useful for epidemiological studies.

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Metabolic Hallmarks for Purine Nucleotide Biosynthesis in Small-Cell Lung Carcinoma

Tabata, S., Umemura, S., Narita, M., Udagawa, H., Ishikawa, T., Tsuboi, M., Goto, K., Ishii, G., Tsuchihara, K., Ochiai, A., Kobayashi, S., Soga, T., Makinoshima, H.

Mol. Cancer Res. (Molecular Cancer Research) 22 ( 1 ) 82 - 93 2024.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 15417786

Small-cell lung cancer (SCLC) has a poor prognosis, emphasizing the necessity for developing new therapies. The de novo synthesis pathway of purine nucleotides, which is involved in the malignant growth of SCLC, has emerged as a novel therapeutic target. Purine nucleotides are supplied by two pathways: de novo and salvage. However, the role of the salvage pathway in SCLC and the differences in utilization and crosstalk between the two pathways remain largely unclear. Here, we found that deletion of the HPRT1 gene, which codes for the rate-limiting enzyme of the purine salvage pathway, significantly suppressed tumor growth in vivo in several SCLC cells. We also demonstrated that HPRT1 expression confers resistance to lemetrexol (LMX), an inhibitor of the purine de novo pathway. Interestingly, HPRT1-knockout had less effect on SCLC SBC-5 cells, which are more sensitive to LMX than other SCLC cell lines, suggesting that a preference for either the purine de novo or salvage pathway occurs in SCLC. Furthermore, metabolome analysis of HPRT1-knockout cells revealed increased intermediates in the pentose phosphate pathway and elevated metabolic flux in the purine de novo pathway, indicating compensated metabolism between the de novo and salvage pathways in purine nucleotide biosynthesis. These results suggest that HPRT1 has therapeutic implications in SCLC and provide fundamental insights into the regulation of purine nucleotide biosynthesis.

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