Details of a Researcher - Soga, Tomoyoshi

Papers - Soga, Tomoyoshi

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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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Human iPSC-derived renal collecting duct organoid model cystogenesis in ADPKD

Mae, S., Hattanda, F., Morita, H., Nozaki, A., Katagiri, N., Ogawa, H., Teranaka, K., Nishimura, Y., Kudoh, A., Yamanaka, S., Matsuse, K., Ryosaka, M., Watanabe, A., Soga, T., Nishio, S., Osafune, K.

Cell Rep. (Cell Reports) 42 ( 12 ) 113431 - 113431 2023.12

Research paper (scientific journal), Joint Work, Accepted

In autosomal dominant polycystic kidney disease (ADPKD), renal cyst lesions predominantly arise from collecting ducts (CDs). However, relevant CD cyst models using human cells are lacking. Although previous reports have generated in vitro renal tubule cyst models from human induced pluripotent stem cells (hiPSCs), therapeutic drug candidates for ADPKD have not been identified. Here, by establishing expansion cultures of hiPSC-derived ureteric bud tip cells, an embryonic precursor that gives rise to CDs, we succeed in advancing the developmental stage of CD organoids and show that all CD organoids derived from PKD1-/- hiPSCs spontaneously develop multiple cysts, clarifying the initiation mechanisms of cystogenesis. Moreover, we identify retinoic acid receptor (RAR) agonists as candidate drugs that suppress in vitro cystogenesis and confirm the therapeutic effects on an ADPKD mouse model in vivo. Therefore, our in vitro CD cyst model contributes to understanding disease mechanisms and drug discovery for ADPKD.

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Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma

Nomura, M., Oh-uchi, M., Sakamoto, Y., Kudo, K., Yaku, K., Soga, T., Sugiura, Y., Morita, M., Hayashi, K., Miyahara, S., Sato, T., Yamashita, Y., Ito, S., Kikuchi, N., Sato, I., Saito, R., Yaegashi, N., Fukuhara, T., Yamada, H., Shima, H., Nakayama, K., Hirao, A., Kawasaki, K., Arai, Y., Akamatsu, S., Tanuma, S., Sato, T., Nakagawa, T., Tanuma, N.

Nat. Commun. (Nature Communications) 14 ( 1 ) 8095 - 8095 2023.12

Research paper (scientific journal), Joint Work, Accepted

Nicotinamide phosphoribosyltransferase (NAMPT) plays a major role in NAD biosynthesis in many cancers and is an attractive potential cancer target. However, factors dictating therapeutic efficacy of NAMPT inhibitors (NAMPTi) are unclear. We report that neuroendocrine phenotypes predict lung and prostate carcinoma vulnerability to NAMPTi, and that NAMPTi therapy against those cancers is enhanced by dietary modification. Neuroendocrine differentiation of tumor cells is associated with down-regulation of genes relevant to quinolinate phosphoribosyltransferase-dependent de novo NAD synthesis, promoting NAMPTi susceptibility in vitro. We also report that circulating nicotinic acid riboside (NAR), a non-canonical niacin absent in culture media, antagonizes NAMPTi efficacy as it fuels NAMPT-independent but nicotinamide riboside kinase 1-dependent NAD synthesis in tumors. In mouse transplantation models, depleting blood NAR by nutritional or genetic manipulations is synthetic lethal to tumors when combined with NAMPTi. Our findings provide a rationale for simultaneous targeting of NAR metabolism and NAMPT therapeutically in neuroendocrine carcinoma.

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Homogeneous luminescent quantitation of cellular guanosine and adenosine triphosphates (GTP and ATP) using QT-LucGTP&ATP assay

Kopra, K., Mahran, R., Yli-Hollo, T., Tabata, S., Vuorinen, E., Fujii, Y., Vuorinen, I., Ogawa-Iio, A., Hirayama, A., Soga, T., Sasaki, AT. Härmä, H.

Anal. Bioanal. Chem. (Analytical and Bioanalytical Chemistry) 415 ( 27 ) 6689 - 6700 2023.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 16182642

Guanosine triphosphate (GTP) and adenosine triphosphate (ATP) are essential nucleic acid building blocks and serve as energy molecules for a wide range of cellular reactions. Cellular GTP concentration fluctuates independently of ATP and is significantly elevated in numerous cancers, contributing to malignancy. Quantitative measurement of ATP and GTP has become increasingly important to elucidate how concentration changes regulate cell function. Liquid chromatography-coupled mass spectrometry (LC-MS) and capillary electrophoresis-coupled MS (CE-MS) are powerful methods widely used for the identification and quantification of biological metabolites. However, these methods have limitations related to specialized instrumentation and expertise, low throughput, and high costs. Here, we introduce a novel quantitative method for GTP concentration monitoring (GTP-quenching resonance energy transfer (QRET)) in homogenous cellular extracts. CE-MS analysis along with pharmacological control of cellular GTP levels shows that GTP-QRET possesses high dynamic range and accuracy. Furthermore, we combined GTP-QRET with luciferase-based ATP detection, leading to a new technology, termed QT-LucGTP&ATP, enabling high-throughput compatible dual monitoring of cellular GTP and ATP in a homogenous fashion. Collectively, GTP-QRET and QT-LucGTP&ATP offer a unique, high-throughput opportunity to explore cellular energy metabolism, serving as a powerful platform for the development of novel therapeutics and extending its usability across a range of disciplines.

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GREB1 isoform 4 is specifically transcribed by MITF and required for melanoma proliferation

Shinzawa, K., Matsumoto, S., Sada, R., Harada, A., Saitoh, K., Kato, K., Ikeda, S., Hirayama, A., Yokoi, K., Tanemura, A., Nimura, K., Ikawa, M., Soga, T., Kikuchi, A.

Oncogene (Oncogene) 42 ( 42 ) 3142 - 3156 2023.10

Research paper (scientific journal), Accepted, ISSN 09509232

Growth regulation by estrogen in breast cancer 1 (GREB1) is involved in hormone-dependent and -independent tumor development (e.g., hepatoblastoma). In this study, we found that a GREB1 splicing variant, isoform 4 (Is4), which encodes C-terminal half of full-length GREB1, is specifically expressed via microphthalmia-associated transcription factor (MITF) in melanocytic melanoma, and that two MITF-binding E-box CANNTG motifs at the 5'-upstream region of GREB1 exon 19 are necessary for GREB1 Is4 transcription. MITF and GREB1 Is4 were strongly co-expressed in approximately 20% of the melanoma specimens evaluated (17/89 cases) and their expression was associated with tumor thickness. GREB1 Is4 silencing reduced melanoma cell proliferation in association with altered expression of cell proliferation-related genes in vitro. In addition, GREB1 Is4 targeting by antisense oligonucleotide (ASO) decreased melanoma xenograft tumor formation and GREB1 Is4 expression in a BRAFV600E; PTENflox melanoma mouse model promoted melanoma formation, demonstrating the crucial role of GREB1 Is4 for melanoma proliferation in vivo. GREB1 Is4 bound to CAD, the rate-limiting enzyme of pyrimidine metabolism, and metabolic flux analysis revealed that GREBI Is4 is necessary for pyrimidine synthesis. These results suggest that MITF-dependent GREB1 Is4 expression leads to melanoma proliferation and GREB1 Is4 represents a new molecular target in melanoma.

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Decreased liver B vitamin-related enzymes as a metabolic hallmark of cancer cachexia

Kojima, Y., Mishiro-Sato, E., Fujishita, T., Satoh, K., Kajino-Sakamoto, R., Oze, I., Nozawa, K., Narita, Y., Ogata, T., Matsuo, K., Muro, K., Taketo, M., Soga, T., Aoki, A.

Nat. Commun. 14 ( 1 ) 6246 - 6246 2023.10

Research paper (scientific journal), Joint Work, Accepted

Cancer cachexia is a complex metabolic disorder accounting for ~20% of cancer-related deaths, yet its metabolic landscape remains unexplored. Here, we report a decrease in B vitamin-related liver enzymes as a hallmark of systemic metabolic changes occurring in cancer cachexia. Metabolomics of multiple mouse models highlights cachexia-associated reductions of niacin, vitamin B6, and a glycine-related subset of one-carbon (C1) metabolites in the liver. Integration of proteomics and metabolomics reveals that liver enzymes related to niacin, vitamin B6, and glycine-related C1 enzymes dependent on B vitamins decrease linearly with their associated metabolites, likely reflecting stoichiometric cofactor-enzyme interactions. The decrease of B vitamin-related enzymes is also found to depend on protein abundance and cofactor subtype. These metabolic/proteomic changes and decreased protein malonylation, another cachexia feature identified by protein post-translational modification analysis, are reflected in blood samples from mouse models and gastric cancer patients with cachexia, underscoring the clinical relevance of our findings.

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Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment

Yabushita, T. Chinen, T., Nishiyama, A., Asada, S., Shimura, R., Isobe, T., Yamamoto, K., Sato, N., Enomoto, Y., Tanaka, Y., Fukuyama, T., Satoh, H., Kato, K., Saitoh, K., Ishikawa, T., Soga, T., Nannya, Y., Fukagawa, T., Nakanishi, M., Kitagawa, D., Kitamura, T., Goyama, S.

Cell Rep. 42 ( 9 ) 113098 - 113098 2023.09

Research paper (scientific journal), Joint Work, Accepted

Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.

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Human acute leukemia uses branched-chain amino acid catabolism to maintain stemness through regulating PRC2 function

Kikushige, Y., Miyamoto, T., Kochi, Y., Semba, Y., Ohishi, M., Irifune, H., Hatakeyama, K., Kunisaki, Y., Sugio, T., Sakoda, T., Miyawaki, K., Kato, K., Soga, T., Akashi, K.

Blood Adv. (Blood Advances) 7 ( 14 ) 3592 - 3603 2023.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 24739529

Cancer-specific metabolic activities play a crucial role in the pathogenesis of human malignancies. To investigate human acute leukemia-specific metabolic properties, we comprehensively measured the cellular metabolites within the CD34+ fraction of normal hematopoietic stem progenitor cells (HSPCs), primary human acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) cells. Here, we show that human leukemia cells are addicted to the branched-chain amino acid (BCAA) metabolism to maintain their stemness, irrespective of myeloid or lymphoid types. Human primary acute leukemias had BCAA transporters for BCAA uptake, cellular BCAA, α-ketoglutarate (α-KG), and cytoplasmic BCAA transaminase-1 (BCAT1) at significantly higher levels than control HSPCs. Isotope-tracing experiments showed that in primary leukemia cells, BCAT1 actively catabolizes BCAA using α-KG into branched-chain α-ketoacids, whose metabolic processes provide leukemia cells with critical substrates for the trichloroacetic acid cycle and the synthesis of nonessential amino acids, both of which reproduce α-KG to maintain its cellular level. In xenogeneic transplantation experiments, deprivation of BCAA from daily diet strongly inhibited expansion, engraftment and self-renewal of human acute leukemia cells. Inhibition of BCAA catabolism in primary AML or ALL cells specifically inactivates the function of the polycomb repressive complex 2, an epigenetic regulator for stem cell signatures, by inhibiting the transcription of PRC components, such as zeste homolog 2 and embryonic ectoderm development. Accordingly, BCAA catabolism plays an important role in the maintenance of stemness in primary human AML and ALL, and molecules related to the BCAA metabolism pathway should be critical targets for acute leukemia treatment.

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Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma

Kitagawa, A., Osawa, T., Noda, M., Kobayashi, Y., Aki, S., Nakano, Y., Saito, T., Shimizu, D., Komatsu, H., Sugaya, M., Takahashi, J., Kosai, K., Takao, S., Motomura, Y., Sato, K., Hu, Q., Fujii, A., Wakiyama, H., Tobo, T., Uchida, H., Sugimachi, K., Shibata, K., Utsunomiya, T., Kobayashi, S., Ishii, H., Hasegawa, T., Masuda, T., Matsui, Y., Niida, A., Soga, T., Suzuki, Y., Miyano, S., Aburatani, H., Doki, Y., Eguchi, H., Mori, M., Nakayama, K., Shimamura, T., Shibata, T., Mimori, K.

Br. J. Cancer 128 ( 12 ) 2206 - 2217 2023.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 00070920

Background: Driver alterations may represent novel candidates for driver gene-guided therapy; however, intrahepatic cholangiocarcinoma (ICC) with multiple genomic aberrations makes them intractable. Therefore, the pathogenesis and metabolic changes of ICC need to be understood to develop new treatment strategies. We aimed to unravel the evolution of ICC and identify ICC-specific metabolic characteristics to investigate the metabolic pathway associated with ICC development using multiregional sampling to encompass the intra- and inter-tumoral heterogeneity.

Methods: We performed the genomic, transcriptomic, proteomic and metabolomic analysis of 39-77 ICC tumour samples and eleven normal samples. Further, we analysed their cell proliferation and viability.

Results: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case exhibited neutral evolution, regardless of their tumour stage. Upregulation of BCAT1 and BCAT2 indicated the involvement of 'Val Leu Ile degradation pathway'. ICCs exhibit the accumulation of ubiquitous metabolites, such as branched-chain amino acids including valine, leucine, and isoleucine, to negatively affect cancer prognosis. We revealed that this metabolic pathway was almost ubiquitously altered in all cases with genomic diversity and might play important roles in tumour progression and overall survival.

Conclusions: We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions.

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Tumor-infiltrating Leukocyte Profiling Defines Three Immune Subtypes of NSCLC with Distinct Signaling Pathways and Genetic Alterations

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

Cancer Res. Commun. (Cancer Research Communications) 3 ( 6 ) 1026 - 1040 2023.06

Research paper (scientific journal), Joint Work, Accepted

Resistance to immune checkpoint blockade remains challenging in patients with non-small cell lung cancer (NSCLC). Tumor-infiltrating leukocyte (TIL) quantity, composition, and activation status profoundly influence responsiveness to cancer immunotherapy. This study examined the immune landscape in the NSCLC tumor microenvironment by analyzing TIL profiles of 281 fresh resected NSCLC tissues. Unsupervised clustering based on numbers and percentages of 30 TIL types classified adenocarcinoma (LUAD) and squamous cell carcinoma (LUSQ) into the cold, myeloid cell-dominant, and CD8+ T cell-dominant subtypes. These were significantly correlated with patient prognosis; the myeloid cell subtype had worse outcomes than the others. Integrated genomic and transcriptomic analyses, including RNA sequencing, whole-exome sequencing, T-cell receptor repertoire, and metabolomics of tumor tissue, revealed that immune reaction-related signaling pathways were inactivated, while the glycolysis and K-ras signaling pathways activated in LUAD and LUSQ myeloid cell subtypes. Cases with ALK and ROS1 fusion genes were enriched in the LUAD myeloid subtype, and the frequency of TERT copy-number variations was higher in LUSQ myeloid subtype than in the others. These classifications of NSCLC based on TIL status may be useful for developing personalized immune therapies for NSCLC.

Significance: The precise TIL profiling classified NSCLC into novel three immune subtypes that correlates with patient outcome, identifying subtype-specific molecular pathways and genomic alterations that should play important roles in constructing subtype-specific immune tumor microenvironments. These classifications of NSCLC based on TIL status are useful for developing personalized immune therapies for NSCLC.

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Tumor cell-derived spermidine is an oncometabolite that suppress TCR clustering for intratumoral CD8+ T cell activation

Hibino, S., Eto, S., Hangai, S., Endo, K., Ashitani, S., Sugaya, M., Osawa, T., Soga, T., Taniguchi, T., Yanai, H.

Proc. Natl. Acad. Sci. USA 120 ( 24 ) e2305245120 - e2305245120 2023.06

Research paper (scientific journal), Joint Work, Accepted

The activation and expansion of T cells that recognize cancer cells is an essential aspect to antitumor immunity. Tumors may escape destruction by the immune system through ectopic expression of inhibitory immune ligands typically exemplified by the PD-L1/PD-1 pathway. Here, we reveal another facet of tumor evasion from T cell surveillance. By secretome profiling of necrotic tumor cells, we identified an oncometabolite spermidine as a unique inhibitor of T cell receptor (TCR) signaling. Mechanistically, spermidine causes the downregulation of the plasma membrane cholesterol levels, resulting in the suppression of TCR clustering. Using syngeneic mouse models, we show that spermidine is abundantly detected in the tumor immune microenvironment (TIME) and that administration of the polyamine synthesis inhibitor effectively enhanced CD8+ T cell–dependent antitumor responses. Further, the combination of the polyamine synthesis inhibitor with anti-PD-1 immune checkpoint antibody resulted in a much stronger antitumor immune response. This study reveals an aspect of immunosuppressive TIME, wherein spermidine functions as a metabolic T cell checkpoint that may offer a unique approach for promoting tumor immunotherapy.

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Quality Control of Targeted Plasma Lipids in a Large-Scale Cohort Study Using Liquid Chromatography–Tandem Mass Spectrometry

Hirayama, A., Ishikawa, T., Takahashi, H., Yamanaka, S., Ikeda, S., Hirata, A., Harada, S., Sugimoto, M., Soga, T., Tomita, M., Takebayashi, T.

Metabolites 13 ( 4 ) 558 - 558 2023.04

Research paper (scientific journal), Joint Work, Accepted

High-throughput metabolomics has enabled the development of large-scale cohort studies. Long-term studies require multiple batch-based measurements, which require sophisticated quality control (QC) to eliminate unexpected bias to obtain biologically meaningful quantified metabolomic profiles. Liquid chromatography–mass spectrometry was used to analyze 10,833 samples in 279 batch measurements. The quantified profile included 147 lipids including acylcarnitine, fatty acids, glucosylceramide, lactosylceramide, lysophosphatidic acid, and progesterone. Each batch included 40 samples, and 5 QC samples were measured for 10 samples of each. The quantified data from the QC samples were used to normalize the quantified profiles of the sample data. The intra- and inter-batch median coefficients of variation (CV) among the 147 lipids were 44.3% and 20.8%, respectively. After normalization, the CV values decreased by 42.0% and 14.7%, respectively. The effect of this normalization on the subsequent analyses was also evaluated. The demonstrated analyses will contribute to obtaining unbiased, quantified data for large-scale metabolomics.

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L-2hydroxyglutaric acid rewires amino acid metabolism in colorectal cancer via the mTOR-ATF4 axis

Tabata, S., Kojima, Y., Sakamoto, T., Igarashi, K., Umetsu, K., Ishikawa, T., Hirayama, A., Kajino-Sakamoto, R., Sakamoto, N., Yasumoto, K., Okano, K., Suzuki, Y., Yachida, S., Aoki, M., Soga, T.

Oncogene 42 ( 16 ) 1294 - 1307 2023.04

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted, ISSN 09509232

Oncometabolites, such as D/L-2-hydroxyglutarate (2HG), have directly been implicated in carcinogenesis; however, the underlying molecular mechanisms remain poorly understood. Here, we showed that the levels of the L-enantiomer of 2HG (L2HG) were specifically increased in colorectal cancer (CRC) tissues and cell lines compared with the D-enantiomer of 2HG (D2HG). In addition, L2HG increased the expression of ATF4 and its target genes by activating the mTOR pathway, which subsequently provided amino acids and improved the survival of CRC cells under serum deprivation. Downregulating the expression of L-2-hydroxyglutarate dehydrogenase (L2HGDH) and oxoglutarate dehydrogenase (OGDH) increased L2HG levels in CRC, thereby activating mTOR-ATF4 signaling. Furthermore, L2HGDH overexpression reduced L2HG-mediated mTOR-ATF4 signaling under hypoxia, whereas L2HGDH knockdown promoted tumor growth and amino acid metabolism in vivo. Together, these results indicate that L2HG ameliorates nutritional stress by activating the mTOR-ATF4 axis and thus could be a potential therapeutic target for CRC.

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