Details of a Researcher - Soga, Tomoyoshi

Papers - Soga, Tomoyoshi

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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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SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia

Hoshii, T., Perlee, S., Kikuchi, S., Rahmutulla, B, Fukuyo, M., Masuda, T., Ohtsuki, S., Soga, T., Nabet, B., Kaneda, A.

Cell Rep. 41 ( 9 ) 111727 2022.11

Research paper (scientific journal), Joint Work, Accepted

Histone methyltransferase SETD1A is critical for acute myeloid leukemia (AML) cell survival, but the molecular mechanism driving SETD1A gene regulation remains elusive. To delineate the role of SETD1A, we utilize a protein degrader technology to induce rapid SETD1A degradation in AML cell lines. SETD1A degradation results in immediate downregulation of transcripts associated with DNA repair and heme biosynthesis pathways. CRISPR-based functional analyses and metabolomics reveal an essential role of SETD1A to maintain mitochondrial respiration in AML cells. These SETD1A targets are enriched in head-to-head (H2H) genes. SETD1A degradation disrupts a non-enzymatic SETD1A domain-dependent cyclin K function, increases the Ser5P RNA polymerase II (RNAPII) at the transcriptional start site (TSS), and induces the promoter-proximal pausing of RNAPII in a strand-specific manner. This study reveals a non-enzymatic role for SETD1A in transcriptional pause release and provides insight into the mechanism of RNAPII pausing and its function in cancer.

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Relationship between [18 F]FDG PET/CT and metabolomics in patients with colorectal cancer

Imajo, M., Norikane, T., Yamamoto, Y., Maeda, Y., Saitoh, K., Kato, K., Soga, T., Okano, K., Nishiyama, Y.

Metabolomics 18 ( 11 ) 91 2022.11

Research paper (scientific journal), Joint Work, Accepted

Introduction: Advances in metabolomics have significantly improved cancer detection, diagnosis, treatment, and prognosis.

Objectives: To investigate the relationship between metabolic tumor volume (MTV) using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET)/ computed tomography (CT) and metabolomics data in patients with colorectal cancer (CRC).

Methods: The metabolome in tumor tissues was analyzed using capillary electrophoresis time-of-flight mass spectrometry in 33 patients with newly diagnosed CRC who underwent FDG PET/CT before treatment and had tumor tissue post-surgery. Based on the FDG PET data, MTV was calculated and was dichotomized according to the median value, and tumors were divided into low-MTV and high-MTV tumors. Metabolomics data were compared between the low-MTV and high-MTV tumors.

Results: The levels of most glycolysis-related metabolites were not different between low-MTV and high-MTV tumors. The level of component of the initial part of the tricarboxylic acid (TCA) cycle, citrate, was significantly lower in the high-MTV tumor than in the low-MTV tumor. The TCA intermediate succinate level was significantly higher in the high-MTV tumor than in the low-MTV tumor. In contrast, the TCA intermediate fumarate level was significantly lower in the high-MTV tumor than in the low-MTV tumor. The levels of many amino acids were significantly higher in the high-MTV tumor than in the low-MTV tumor.

Conclusions: Although preliminary, these results suggest that tumors with high FDG metabolism in CRC may obtain more energy by using a reverse reaction of the TCA cycle and amino-acid metabolism. However, further research is required to clarify this relationship.

Keywords: Colorectal cancer; FDG; Metabolome; PET/CT.

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Comprehensive metabolome analysis of intracellular metabolites in cultured cells

Kudo, R., Igarashi, K., Soga, T., Ishikawa, T., Saito, Y.

STAR Protoc. 3 ( 3 ) 101531 2022.09

Research paper (scientific journal), Joint Work, Accepted

Capillary electrophoresis mass spectrometry (CE-MS) can measure the intracellular amount of highly polar and charged metabolites; liquid chromatography mass spectrometry (LC-MS) can quantify hydrophobic metabolites. A comprehensive metabolome analysis requires independent sample preparation for LC-MS and CE-MS. Here, we present a protocol to prepare for sequentially analyzing the metabolites from one sample. Here we describe the steps for breast cancer cell lines, MCF-7 cells, but the protocol can be applied to other cell types.

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Development of Fluorophosphoramidate as a Biocompatibly Transformable Functional Group and its Application as a Phosphate Prodrug for Nucleoside Analogs

Yoshida, Y., Zheng, T., Tanabe, W., Tomoike, F., Hashiya, F., Suzuki, T., Hirota, S., Saiki, Y., Horii, A., Hirayama, A., Soga, T., Kimura, Y., Abe, H.

ChemMedChem 17 ( 17 ) e202200188 2022.09

Research paper (scientific journal), Joint Work, Accepted

Synthetic phosphate-derived functional groups are important for controlling the function of bioactive molecules in vivo. Herein we describe the development of a new type of biocompatible phosphate analog, a fluorophosphoramidate (FPA) functional group that has characteristic P-F and P-N bonds. We found that FPA with a primary amino group was relatively unstable in aqueous solution and was converted to a monophosphate, while FPA with a secondary amino group was stable. Furthermore, by improving the molecular design of FPA, we developed a reaction in which a secondary amino group is converted to a primary amino group in the intracellular environment and clarified that the FPA group functions as a phosphate prodrug of nucleoside. Various FPA-gemcitabine derivatives were synthesized and their toxicity to cancer cells were evaluated. One of the FPA-gemcitabine derivatives showed superior toxicity compared with gemcitabine and its ProTide prodrug, which methodology is widely used in various nucleoside analogs, including anti-cancer and anti-virus drugs.

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Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N-oxide-dependent mechanism

Yoshida, Y., Shimizu, I., Shimada, A., Nakahara, K., Yanagisawa, S., Kubo, M., Fukuda, S., Ishii, C., Yamamoto, H., Ishikawa, T., Kano, K., Aoki, J., Katsuumi, G., Suda, M., Ozaki, K., Yoshida, Y., Okuda, S., Ohta, S., Okamoto, S., Minokoshi, Y., Oda, K., Sasaoka, T., Abe, M., Sakimura, K., Kubota, Y., Yoshimura, N., Kajimura, S., Zuriaga, M., Walsh, K., Soga, T., Minamino, T.

Sci. Rep. 12 14883 2022.09

Research paper (scientific journal), Joint Work, Accepted

Low body temperature predicts a poor outcome in patients with heart failure, but the underlying pathological mechanisms and implications are largely unknown. Brown adipose tissue (BAT) was initially characterised as a thermogenic organ, and recent studies have suggested it plays a crucial role in maintaining systemic metabolic health. While these reports suggest a potential link between BAT and heart failure, the potential role of BAT dysfunction in heart failure has not been investigated. Here, we demonstrate that alteration of BAT function contributes to development of heart failure through disorientation in choline metabolism. Thoracic aortic constriction (TAC) or myocardial infarction (MI) reduced the thermogenic capacity of BAT in mice, leading to significant reduction of body temperature with cold exposure. BAT became hypoxic with TAC or MI, and hypoxic stress induced apoptosis of brown adipocytes. Enhancement of BAT function improved thermogenesis and cardiac function in TAC mice. Conversely, systolic function was impaired in a mouse model of genetic BAT dysfunction, in association with a low survival rate after TAC. Metabolomic analysis showed that reduced BAT thermogenesis was associated with elevation of plasma trimethylamine N-oxide (TMAO) levels. Administration of TMAO to mice led to significant reduction of phosphocreatine and ATP levels in cardiac tissue via suppression of mitochondrial complex IV activity. Genetic or pharmacological inhibition of flavin-containing monooxygenase reduced the plasma TMAO level in mice, and improved cardiac dysfunction in animals with left ventricular pressure overload. In patients with dilated cardiomyopathy, body temperature was low along with elevation of plasma choline and TMAO levels. These results suggest that maintenance of BAT homeostasis and reducing TMAO production could be potential next-generation therapies for heart failure.

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Salivary metabolomics with machine learning for colorectal cancer detection

Kuwabara, H., Katsumata, K., Iwabuthi, A., Udo, R., Tago, T., Kasahara, K., Mazaki, J., Enomoto, M., Ishizaki, T., Soya, R., Kaneko, M., Ota, S., Enomoto, A., Soga, T., Tomita, M., Sunamura, M., Tsuchida, A., Sugimoto, M., Nagakawa, Y.

Cancer Sci. 113 ( 9 ) 3234 - 3243 2022.09

Research paper (scientific journal), Joint Work, Accepted

As the worldwide prevalence of colorectal cancer (CRC) increases, it is vital to reduce its morbidity and mortality through early detection. Saliva-based tests are an ideal noninvasive tool for CRC detection. Here, we explored and validated salivary biomarkers to distinguish patients with CRC from those with adenoma (AD) and healthy controls (HC). Saliva samples were collected from patients with CRC, AD, and HC. Untargeted salivary hydrophilic metabolite profiling was conducted using capillary electrophoresis–mass spectrometry and liquid chromatography–mass spectrometry. An alternative decision tree (ADTree)-based machine learning (ML) method was used to assess the discrimination abilities of the quantified metabolites. A total of 2,602 unstimulated saliva samples were collected from subjects with CRC (n = 231), AD (n = 54), and HC (n = 2,317). Data were randomly divided into training (n = 1,301) and validation datasets (n = 1,301). The clustering analysis showed a clear consistency of aberrant metabolites between the two groups. The ADTree model was optimized through cross-validation (CV) using the training dataset, and the developed model was validated using the validation dataset. The model discriminating CRC + AD from HC showed area under the receiver operating characteristic curves (AUC) of 0.860 (95% confidence interval [CI]: 0.828-0.891) for CV and 0.870 (95% CI: 0.837-0.903) for the validation dataset. The other model discriminating CRC from AD + HC showed an AUC of 0.879 (95% CI: 0.851-0.907) and 0.870 (95% CI: 0.838 - 0.902), respectively. Salivary metabolomics combined with ML demonstrated high accuracy and versatility in detecting CRC.

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In vivo transomic analyses of glucose-responsive metabolism in skeletal muscle reveal core differences between the healthy and obese states

Kokaji, T., Eto, M., Hatano, A., Yugi K., Morita, K., Ohno, S., Fujii, M., Hironaka, K., Ito, Y., Egami, R., Uematsu, S., Terakawa, A., Pan, Y., Maehara, H., Li, D., Bai, Y., Tsuchiya, T., Ozaki, H., Inoue, H., Kubota, H., Suzuki, Y., Hirayama, A., Soga, T., Kuroda, S.

Sci. Rep. 12 13719 2022.08

Research paper (scientific journal), Joint Work, Accepted

Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and leptin-deficient obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.

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Tumor metabolic alterations after neoadjuvant chemoradiotherapy predict postoperative recurrence in patients with pancreatic cancer

Wada, Y., Okano, K., Sato, K., Sugimoto, M., Shimomura, A., Nagao, M., Matsukawa, H., Ando, Y., Suto, H., Oshima, M., Kondo, A., Asano, E., Kishino, T., Kumamoto, K., Kobara, H., Kamada, H., Masaki, T., Soga, T., Suzuki, Y.

Jpn J Clin Oncol. 52 ( 8 ) 879 - 887 2022.08

Research paper (scientific journal), Joint Work, Accepted

Objective: We investigated the metabolic changes in pancreatic ductal adenocarcinoma to identify the mechanisms of treatment response of neoadjuvant chemoradiation therapy.

Methods: Frozen tumor and non-neoplastic pancreas tissues were prospectively obtained from 88 patients with pancreatic ductal adenocarcinoma who underwent curative-intent surgery. Sixty-two patients received neoadjuvant chemoradiation therapy and 26 patients did not receive neoadjuvant therapy (control group). Comprehensive analysis of metabolites in tumor and non-neoplastic pancreatic tissue was performed by capillary electrophoresis-mass spectrometry.

Results: Capillary electrophoresis-mass spectrometry detected 90 metabolites for analysis among more than 500 ionic metabolites quantified. There were significant differences in 27 tumor metabolites between the neoadjuvant chemoradiation therapy and control groups. There were significant differences in eight metabolites [1-MethylnNicotinamide, Carnitine, Glucose, Glutathione (red), N-acetylglucosamine 6-phosphate, N-acetylglucosamine 1-phosphate, UMP, Phosphocholine] between good responder and poor responder for neoadjuvant chemoradiation therapy. Among these metabolites, phosphocholine, Carnitine and Glutathione were associated with recurrence-free survival only in the neoadjuvant chemoradiation therapy group. Microarray confirmed marked gene suppression of choline transporters [CTL1-4 (SLC44A1-44A4)] in pancreatic ductal adenocarcinoma tissue of neoadjuvant chemoradiation therapy group.

Conclusion: The present study identifies several important metabolic consequences and potential neoadjuvant chemoradiation therapy targets in pancreatic ductal adenocarcinoma. Choline metabolism is one of the key pathways involved in recurrence of the patients with pancreatic ductal adenocarcinoma who received neoadjuvant chemoradiation therapy.

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Glutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors

Pan, M., Zorbas, C., Sugaya, M., Ishiguro, K., Kato, M., Nishida, M., Zhang, H.F., Candeias, M.M., Okamoto, A., Ishikawa, T., Soga, T., Aburatani, H., Sakai, J., Matsumura, Y., Suzuki, T., Proud, C.G., Lafontaine, D.L.J., Osawa, T.

Nat Commun. 13 ( 1 ) 3706 2022.06

Research paper (scientific journal), Joint Work, Accepted

Ribosome biogenesis is an energetically expensive program that is dictated by nutrient availability. Here we report that nutrient deprivation severely impairs precursor ribosomal RNA (pre-rRNA) processing and leads to the accumulation of unprocessed rRNAs. Upon nutrient restoration, pre-rRNAs stored under starvation are processed into mature rRNAs that are utilized for ribosome biogenesis. Failure to accumulate pre-rRNAs under nutrient stress leads to perturbed ribosome assembly upon nutrient restoration and subsequent apoptosis via uL5/uL18-mediated activation of p53. Restoration of glutamine alone activates p53 by triggering uL5/uL18 translation. Induction of uL5/uL18 protein synthesis by glutamine is dependent on the translation factor eukaryotic elongation factor 2 (eEF2), which is in turn dependent on Raf/MEK/ERK signaling. Depriving cells of glutamine prevents the activation of p53 by rRNA synthesis inhibitors. Our data reveals a mechanism that tumor cells can exploit to suppress p53-mediated apoptosis during fluctuations in environmental nutrient availability.

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Comparative Metabolomics of Small Molecules Specifically Expressed in the Dorsal or Ventral Marginal Zones in Vertebrate Gastrula

Suzuki, Y., Hayasaka, R., Hasebe, M., Ikeda, S., Soga, T., Tomita, M., Hirayama, A., Kuroda, H.

Metabolites 12 ( 6 ) 566 2022.06

Research paper (scientific journal), Joint Work, Accepted

Many previous studies have reported the various proteins specifically secreted as inducers in the dorsal or ventral regions in vertebrate gastrula. However, little is known about the effect on cell fate of small molecules below 1000 Da. We therefore tried to identify small molecules specifically expressed in the dorsal marginal zone (DMZ) or ventral marginal zone (VMZ) in vertebrate gastrula. Small intracellular and secreted molecules were detected using explants and supernatant samples. Hydrophilic metabolites were analyzed by capillary ion chromatography–mass spectrometry and liquid chromatography–mass spectrometry, and lipids were analyzed by supercritical fluid chromatography–tandem mass spectrometry. In total, 190 hydrophilic metabolites and 396 lipids were identified. The DMZ was found to have high amounts of glycolysis- and glutathione metabolism-related metabolites in explants, and the VMZ was richer in purine metabolism-related metabolites. We also discovered some hydrophilic metabolites and lipids differentially contained in the DMZ or VMZ. Our research would contribute to a deeper understanding of the cellular physiology that regulates early embryogenesis.

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AGE/RAGE axis regulates reversible transition to quiescent states of ALK-rearranged NSCLC and pancreatic cancer cells in monolayer cultures

Kadonosono, T., Miyamoto, K., Sasaki, S., Matsuo, Y., Kitajima, S., Wang, Q., Endo, M., Nibori, M., Kuchimaru, T., Soga, T., Hirota, K., Kizaka-Kondoh, S.

Sci. Rep. 12 9886 2022.06

Research paper (scientific journal), Joint Work, Accepted

Cancer recurrence due to tumor cell quiescence after therapy and long-term remission is associated with cancer-related death. Previous studies have used cell models that are unable to return to a proliferative state; thus, the transition between quiescent and proliferative states is not well understood. Here, we report monolayer cancer cell models wherein the human non-small cell lung carcinoma cell line H2228 and pancreatic cancer cell line AsPC-1 can be reversibly induced to a quiescent state under hypoxic and serum-starved (HSS) conditions. Transcriptome and metabolome dual-omics profiles of these cells were compared with those of the human lung adenocarcinoma cell line A549, which was unable to enter a quiescent state under HSS conditions. The quiescence-inducible cells had substantially lower intracellular pyruvate and ATP levels in the quiescent state than in the proliferative state, and their response to sudden demand for energy was dramatically reduced. Furthermore, in quiescence-inducible cells, the transition between quiescent and proliferative states of these cells was regulated by the balance between the proliferation-promoting Ras and Rap1 signaling and the suppressive AGE/RAGE signaling. These cell models elucidate the transition between quiescent and proliferative states, allowing the development of drug-screening systems for quiescent tumor cells.

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Different types of reactions to E7386 among colorectal cancer patient-derived organoids and corresponding CAFs

Imai, T., Naruse, M., Ochiai M., Matsumoto K., Ikeda S., Kani, M., Kato, Y., Hirayama, A., Soga, T., Hori, Y., Yokoi, A., Ochiai, A.

Oncol. Lett. 24 ( 1 ) 221 2022.05

Research paper (scientific journal), Joint Work, Accepted

Colorectal cancer (CRC) harbors genetic alterations in a component of the Wnt signaling pathway in ~90% of cases. In addition, the Wnt signaling pathway has been previously suggested to serve a notable role in the pathophysiology of CRC cells and cancer‑associated fibroblasts (CAFs). In the present study, the possible effects of E7386, a selective inhibitor of the interaction between β‑catenin and the cAMP response element‑binding protein‑binding protein, were evaluated using organoids and the corresponding CAFs derived from patients with CRC. E7386 at 100 nM was revealed to decrease the viability of CRC organoids and CAFs. Analysis of the gene expression profiles revealed marked changes in the expression levels of different types of cancer‑associated genes associated with E7386 concentrations in the organoids and/or CAFs, such as those regulating glucose and amino acid metabolism [phosphoenolpyruvate carboxykinase 2, asparagine synthetase (glutamine‑hydrolyzing), phosphoserine aminotransferase 1 and phosphoglycerate dehydrogenase], stimulation of natural killer cell‑mediated cytotoxicity (UL16‑binding protein 1) and modification of the Wnt/β‑catenin signaling pathway (indicated by very low density lipoprotein receptor). Results of the hydrophilic metabolome analysis in the organoids were consistent with those of the transcriptomic analysis. In vivo experiments used corresponding xenograft models, although changes in volume of tumor tissues could not be observed at 50 mg/kg body weight twice a day for 14 days, results on the protein expression levels partially supported those in the in vitro experiments. In conclusion, different types of reactions, such as alterations in the glucose and amino acid metabolic pathways, stimulation of stress responses and NK‑cell mediated cytotoxicity and components in the Wnt/β‑catenin signaling pathway, to E7386 in the CRC organoids and corresponding CAFs were observed under conditions with decreased cell viability. However, further mechanistic studies to clarify the relationships with Wnt/β‑catenin signaling pathway and these reactions using preclinical models and biomarker studies using clinical human samples are required for verification of the present preclinical biomarkers.

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