Details of a Researcher - Soga, Tomoyoshi

Papers - Soga, Tomoyoshi

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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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Comparison of hepatic responses to glucose perturbation between healthy and obese mice based on the edge type of network structures

Ito, Y., Uda, S., Kokaji, T., Hirayama, A., Soga, T., Suzuki, Y., Kuroda, S., Kuroda, H.

Sci. Rep. 13 ( 1 ) 4758 - 4758 2023.03

Research paper (scientific journal), Joint Work, Accepted

Interactions between various molecular species in biological phenomena give rise to numerous networks. The investigation of these networks, including their statistical and biochemical interactions, supports a deeper understanding of biological phenomena. The clustering of nodes associated with molecular species and enrichment analysis is frequently applied to examine the biological significance of such network structures. However, these methods focus on delineating the function of a node. As such, in-depth investigations of the edges, which are the connections between the nodes, are rarely explored. In the current study, we aimed to investigate the functions of the edges rather than the nodes. To accomplish this, for each network, we categorized the edges and defined the edge type based on their biological annotations. Subsequently, we used the edge type to compare the network structures of the metabolome and transcriptome in the livers of healthy (wild-type) and obese (ob/ob) mice following oral glucose administration (OGTT). The findings demonstrate that the edge type can facilitate the characterization of the state of a network structure, thereby reducing the information available through datasets containing the OGTT response in the metabolome and transcriptome.

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Hepatic phosphatidylcholine catabolism driven by PNPLA7 and PNPLA8 supplies endogenous choline to replenish the methionine cycle with methyl groups

Hirabayashi, T., Kawaguchi1, M., †Harada, S., Mouri, M., Takamiya, R., Yoshimi, M., Sato, H., Taketomi, Y., Yokoyama, K., Kobayashi, T., Tokuoka, S.M., Kita, Y., Yoda, E., Hara, S., Mikami, K., Nishito, Y., Kikuchi, N., Nakata, R., Kaneko, M., Kiyonari, H., Kasahara, K., Aiba, T., Ohsako, S., Ikeda, K., Soga, T., Kurano, M., Yatomi, Y., Murakami, M.

Cell Rep. 42 ( 2 ) 111940 2023.02

Research paper (scientific journal), Joint Work, Accepted

Choline supplies methyl groups for regeneration of methionine and the methyl donor S-adenosylmethionine in the liver. Here, we report that the catabolism of membrane phosphatidylcholine (PC) into water-soluble glycerophosphocholine (GPC) by the phospholipase/lysophospholipase PNPLA8-PNPLA7 axis enables endogenous choline stored in hepatic PC to be utilized in methyl metabolism. PNPLA7-deficient mice show marked decreases in hepatic GPC, choline, and several metabolites related to the methionine cycle, accompanied by various signs of methionine insufficiency, including growth retardation, hypoglycemia, hypolipidemia, increased energy consumption, reduced adiposity, increased fibroblast growth factor 21 (FGF21), and an altered histone/DNA methylation landscape. Moreover, PNPLA8-deficient mice recapitulate most of these phenotypes. In contrast to wild-type mice fed a methionine/choline-deficient diet, both knockout strains display decreased hepatic triglyceride, likely via reductions of lipogenesis and GPC-derived glycerol flux. Collectively, our findings highlight the biological importance of phospholipid catabolism driven by PNPLA8/PNPLA7 in methyl group flux and triglyceride synthesis in the liver.

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Optogenetic decoding of Akt2-regulated metabolic signaling pathways in skeletal muscle cells using transomics analysis

Kawamura, G., Kokaji, T., Kawata, K., Sekine, Y., Suzuki, Y., Soga, T., Ueda, Y., Endo, M., Kuroda, S., Ozawa, T.

Sci Signal 16 ( 773 ) eabn0782 - eabn0782 2023.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 19450877

Insulin regulates various cellular metabolic processes by activating specific isoforms of the Akt family of kinases. Here, we elucidated metabolic pathways that are regulated in an Akt2-dependent manner. We constructed a transomics network by quantifying phosphorylated Akt substrates, metabolites, and transcripts in C2C12 skeletal muscle cells with acute, optogenetically induced activation of Akt2. We found that Akt2-specific activation predominantly affected Akt substrate phosphorylation and metabolite regulation rather than transcript regulation. The transomics network revealed that Akt2 regulated the lower glycolysis pathway and nucleotide metabolism and cooperated with Akt2-independent signaling to promote the rate-limiting steps in these processes, such as the first step of glycolysis, glucose uptake, and the activation of the pyrimidine metabolic enzyme CAD. Together, our findings reveal the mechanism of Akt2-dependent metabolic pathway regulation, paving the way for Akt2-targeting therapeutics in diabetes and metabolic disorders.

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NRF3 activates mTORC1 arginine-dependently for cancer cell viability

Hirose, S., Waku, T., Tani, M., Masuda, H., Endo, K., Ashitani, S., Aketa, I., Kitano, H., Nakada, S., Wada, A., Hatanaka, A., Osawa, T., Soga, T., Kobayashi, A.

iScience 26 ( 2 ) 106045 2023.02

Research paper (scientific journal), Joint Work, Accepted

Cancer cells coordinate the mTORC1 signals and the related metabolic pathways to robustly and rapidly grow in response to nutrient conditions. Although a CNC-family transcription factor NRF3 promotes cancer development, the biological relevance between NRF3 function and mTORC1 signals in cancer cells remains unknown. Hence, we showed that NRF3 contributes to cancer cell viability through mTORC1 activation in response to amino acids, particularly arginine. NRF3 induced SLC38A9 and RagC expression for the arginine-dependent mTORC1 recruitment onto lysosomes, and it also enhanced RAB5-mediated bulk macropinocytosis and SLC7A1-mediated selective transport for arginine loading into lysosomes. Besides, the inhibition of the NRF3–mTORC1 axis impaired mitochondrial function, leading to cancer cell apoptosis. Consistently, the aberrant upregulation of the axis caused tumor growth and poor prognosis. In conclusion, this study sheds light on the unique function of NRF3 in arginine-dependent mTORC1 activation and the pathophysiological aspects of the NRF3–mTORC1 axis in cancer development.

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Mitochondria directly sense osmotic stress to trigger rapid metabolic remodeling via regulation of pyruvate dehydrogenase phosphorylation

Ikizawa, T., Ikeda, K., Arita, M., Kitajima, S., Soga, T., Ichijo, H., Naguro, I.

J. Biol. Chem. 299 ( 2 ) 102837 2023.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 00219258

A high-salt diet significantly impacts various diseases, ilncluding cancer and immune diseases. Recent studies suggest that the high-salt/hyperosmotic environment in the body may alter the chronic properties of cancer and immune cells in the disease context. However, little is known about the acute metabolic changes in hyperosmotic stress. Here, we found that hyperosmotic stress for a few minutes induces Warburg-like metabolic remodeling in HeLa and Raw264.7 cells and suppresses fatty acid oxidation. Regarding Warburg-like remodeling, we determined that the pyruvate dehydrogenase phosphorylation status was altered bidirectionally (high in hyperosmolarity and low in hypoosmolarity) to osmotic stress in isolated mitochondria, suggesting that mitochondria themselves have an acute osmosensing mechanism. Additionally, we demonstrate that Warburg-like remodeling is required for HeLa cells to maintain ATP levels and survive under hyperosmotic conditions. Collectively, our findings suggest that cells exhibit acute metabolic remodeling under osmotic stress via the regulation of pyruvate dehydrogenase phosphorylation by direct osmosensing within mitochondria.

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Metabolomics of small extracellular vesicles derived from isocitrate dehydrogenase 1-mutant HCT116 cells collected by semi-automated size exclusion chromatography

Hayasaka, R., Tabata, S., Hasebe, M., Ikeda, S., Hikita, T., Oneyama, C., Yoshitake, J., Onoshima, D., Takahashi, K., Shibata, T., Uchida, K., Baba, Y.., Soga, T., Tomita, M., Hirayama, A.

Front. Mol. Biosci. 9 1049402 2023.01

Research paper (scientific journal), Joint Work, Accepted

Cancer-derived small extracellular vesicles (sEVs) are multifunctional particles with a lipid bilayer structure that are involved in cancer progression, such as malignant proliferation, distant metastasis, and cancer immunity evasion. The separation protocol used to isolate sEVs is an important process and thus, several have been developed, including ultracentrifugation (UC), size exclusion chromatography (SEC), and affinity purification using antibodies against sEV surface antigens. However, the effects of different separation methods on sEV components have not been adequately examined. Here, we developed a semi-automated system for collecting sEVs by combining SEC and preparative high-performance liquid chromatography and applied it to metabolome analysis. The developed SEC system could recover sEVs more efficiently and non-destructively than UC, suggesting that it is an appropriate recovery method for metabolic analysis and reflects biological conditions. Furthermore, using the developed SEC system, we performed metabolome analysis of sEVs from isocitrate dehydrogenase 1 (IDH)-mutated human colon HCT116 cells, which produce the oncogenic metabolite, 2-hydroxyglutaric acid (2-HG). IDH1-mutated HCT116 cells released significantly more sEVs than wild-type (WT) cells. The metabolomic profiles of IDH1 mutant and WT cells showed distinct differences between the cells and their sEVs. Notably, in IDH mutant cells, large amounts of 2-HG were detected not only in cells, but also in sEVs. These results indicate that the SEC system we developed has wide potential applications in sEVs research.

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Advances in capillary electrophoresis mass spectrometry for metabolomics

Soga, T.

Trends Anal. Chem. 158 116883 2023.01

Research paper (scientific journal), Single Work, Accepted, ISSN 01659936

Capillary electrophoresis mass spectrometry (CE-MS) is now regarded as a powerful tool for the comprehensive analysis of low-molecular-weight charged metabolites. Over the past decades, several CE-MS methods have been established and made significant contributions to metabolomics research in various areas. This review describes the general strategies and principles of the CE-MS-based metabolomics analyses, including sample preparation, CE separation modes, interfacing techniques, and mass spectrometers. Furthermore, new techniques to increase throughput ability in CE-MS for metabolomics are highlighted. Finally, general conclusions and perspectives are provided.

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Interleukin-6 blockade reduces salt-induced cardiac inflammation and fibrosis in subtotal nephrectomized mice

Tanaka, H., Sun, T., Kinashi, H., Kamiya, K., Yamaguchi, M., Nobata, H., Sakata, F., Kim, H., Mizuno, M., Kunoki, S., Sakai, Y., Hirayama, A., Soga, T., Yoshikawa, K., Ishimoto, T., Ito, Y.

Am. J. Physiol. Renal Physiol. 323 ( 6 ) F654 - F665 2022.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 1931857X

Cardiovascular disease is the most common comorbidity in patients with chronic kidney disease (CKD), affecting both their prognosis and quality of life. Cardiac fibrosis is common in patients with CKD with left ventricular diastolic dysfunction, and it is associated with increased risk of heart failure and mortality. Recent evidence suggests that high salt intake activates immune responses associated with local accumulation of sodium. We reported that high salt intake promotes cardiac inflammation in subtotal nephrectomized (Nx) mice. We investigated the effects of administration of MR16-1, a rat anti-mouse monoclonal interleukin (IL)-6 receptor antibody, in Nx mice with salt loading (Nx-salt). Expression of monocyte chemoattractant protein-1, tumor necrosis factor-α, IL-1β, and IL-6 mRNAs and macrophage infiltration was significantly reduced in the heart of Nx-salt mice treated with MR16-1 (Nx-salt-MR16-1) compared with Nx-salt mice treated with control rat rat IgG1 (Nx-salt-rat IgG1). Correspondingly, cardiac fibrosis was significantly attenuated in Nx-salt-MR16-1 mice compared with Nx-salt-rat IgG1 mice. Furthermore, in the heart of Nx-salt-MR16-1 mice, expression of mRNA for nicotinamide adenine dinucleotide phosphate oxidase-2, an oxidative stress marker, was significantly downregulated compared with Nx-salt-rat IgG1 mice. Increases in cardiac metabolites, including histidine and γ-butyrobetaine, were also reversed by IL-6 blockade treatment. In conclusion, IL-6 blockade exerts anti-inflammatory, antifibrotic, and partial antioxidative effects in the heart of Nx-salt mice.NEW & NOTEWORTHY In the present study, IL-6 blockade exerted anti-inflammatory, antifibrotic, and partial antioxidative effects on the hearts of mice with CKD on a high-salt diet. Therefore, IL-6 potentially mediates cardiac fibrosis induced by high salt intake in patients with CKD, a finding with therapeutic implications. Of note, the next therapeutic implication may simply be the reinforcement of low-salt diets or diuretics and further research on the anti-inflammatory effects of these measures rather than IL-6 blockade with high-salt diet.

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