Kubota, Naoto

写真a

Affiliation

School of Medicine, Division of Diagnostic Pathology (Shinanomachi)

Position

Instructor

External Links
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Profile Summary 【 Display / hide 】

  • 病理形態学に基づく病態の解析を基本とし、特に肝胆膵分野を中心とした研究を行っている。

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Career 【 Display / hide 】

  • 2006.04
    -
    2012.03

    Keio University of Medicine, Student

  • 2012.04
    -
    2014.03

    Tokyo Medical Center, medical intern

  • 2014.04
    -
    2018.03

    Keio University of Medicine, Pathology, graduate student

  • 2018.04
    -
    2019.03

    Keio University, 医学部病理学教室, 助教

  • 2019.04
    -
    2020.03

    NIPPON KOUKAN HOSPITAL

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Academic Background 【 Display / hide 】

  • 2006.04
    -
    2012.03

    Keio University, Medical faculty

    University, Graduated, Other

  • 2014.04
    -
    2018.03

    Keio University

    Graduate School, Withdrawal after completion of doctoral course requirements, Doctoral course

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Academic Degrees 【 Display / hide 】

  • PhD (Medical science), Keio University, Coursework, 2020.03

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Licenses and Qualifications 【 Display / hide 】

  • Medical doctor, 2012.04

  • 死体解剖資格, 2016.11

  • Pathologist, 2018.08

  • cytology specialist, 2019.01

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Research Areas 【 Display / hide 】

  • Life Science / Genome biology (transcriptome analysis)

  • Life Science / Human pathology

  • Life Science / Experimental pathology

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Research Keywords 【 Display / hide 】

  • Pathology

  • Hepatology

  • Biliary Disease

  • Oncology

  • Pancreatic Disease

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Research Themes 【 Display / hide 】

  • Hepatocellular carcinoma, 

    2014.04
    -
    Present

  • Billiary cancer, 

    2014.04
    -
    Present

  • Pancreatic cancer, 

    2014.04
    -
    Present

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Books 【 Display / hide 】

  • Liver cancer risk-predictive molecular biomarkers specific to clinico-epidemiological contexts

    Kubota N, Fujiwara N, Hoshida Y, Advances in Cancer Research, 2022.01

    　View Summary

    Hepatocellular carcinoma (HCC) risk prediction is increasingly important because of the low annual HCC incidence in patients with the rapidly emerging non-alcoholic fatty liver disease or cured HCV infection. To date, numerous clinical HCC risk biomarkers and scores have been reported in literature. However, heterogeneity in clinico-epidemiological context, e.g., liver disease etiology, patient race/ethnicity, regional environmental exposure, and lifestyle-related factors, obscure their real clinical utility and applicability. Proper characterization of these factors will help refine HCC risk prediction according to certain clinical context/scenarios and contribute to improved early HCC detection. Molecular factors underlying the clinical heterogeneity encompass various features in host genetics, hepatic and systemic molecular dysregulations, and cross-organ interactions, which may serve as clinical-context-specific biomarkers and/or therapeutic targets. Toward the goal to enable individual-risk-based HCC screening by incorporating the HCC risk biomarkers/scores, their assessment in patient with well-defined clinical context/scenario is critical to gauge their real value and to maximize benefit of the tailored patient management for substantial improvement of the poor HCC prognosis.

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Papers 【 Display / hide 】

  • Activating an Adaptive Immune Response with a Telomerase-Mediated Telomere Targeting Therapeutic in Hepatocellular Carcinoma

    Mender I, Siteni S, Barron S, Flusche A.M, Kubota N, Yu C, Cornelius C, Tedone E, Maziveyi M, Grichuk A, Venkateswaran N, Conacci-Sorrell M, Hoshida Y, Kang R, Tang D, Gryaznov S, Shay J.W

    Molecular cancer therapeutics (Molecular cancer therapeutics)  22 ( 6 ) 737 - 750 2023.06

    ISSN  1535-7163

    　View Summary

    A select group of patients with hepatocellular carcinomas (HCC) benefit from surgical, radiologic, and systemic therapies that include a combination of anti-angiogenic and immune-checkpoint inhibitors. However, because HCC is generally asymptomatic in its early stages, this not only leads to late diagnosis, but also to therapy resistance. The nucleoside analogue 6-thio-dG (THIO) is a first-in-class telomerase-mediated telomere-targeting anticancer agent. In telomerase expressing cancer cells, THIO is converted into the corresponding 5'-triphosphate, which is efficiently incorporated into telomeres by telomerase, activating telomere damage responses and apoptotic pathways. Here, we show how THIO is effective in controlling tumor growth and, when combined with immune checkpoint inhibitors, is even more effective in a T-cell-dependent manner. We also show telomere stress induced by THIO increases both innate sensing and adaptive antitumor immunity in HCC. Importantly, the extracellular high-mobility group box 1 protein acts as a prototypical endogenous DAMP (Damage Associated Molecular Pattern) in eliciting adaptive immunity by THIO. These results provide a strong rationale for combining telomere-targeted therapy with immunotherapy.

  • Data from Activating an Adaptive Immune Response with a Telomerase-Mediated Telomere Targeting Therapeutic in Hepatocellular Carcinoma

     2023.06

  • A Therapeutically Targetable TAZ-TEAD2 Pathway Drives the Growth of Hepatocellular Carcinoma via ANLN and KIF23

    Saito Y, Yin D, Kubota N, Wang X, Filliol A, Remotti H, Nair A, Fazlollahi L, Hoshida Y, Tabas I, Wangensteen K.J, Schwabe R.F

    Gastroenterology (Gastroenterology)  164 ( 7 ) 1279 - 1292 2023.06

    ISSN  00165085

    　View Summary

    Background & Aims: Despite recent progress, long-term survival remains low for hepatocellular carcinoma (HCC). The most effective HCC therapies target the tumor immune microenvironment (TIME), and there are almost no therapies that directly target tumor cells. Here, we investigated the regulation and function of tumor cell-expressed Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in HCC. Methods: HCC was induced in mice by Sleeping Beauty-mediated expression of MET, CTNNB1-S45Y, or TAZ-S89A, or by diethylnitrosamine plus CCl4. Hepatocellular TAZ and YAP were deleted in floxed mice via adeno-associated virus serotype 8-mediated expression of Cre. TAZ target genes were identified from RNA sequencing, confirmed by chromatin immunoprecipitation, and evaluated in a clustered regularly interspaced short palindromic repeats interference (CRISPRi) screen. TEA domain transcription factors (TEADs), anillin (ANLN), Kif23, and programmed cell death protein ligand 1 were knocked down by guide RNAs in dead clustered regularly interspaced short palindromic repeats–associated protein 9 (dCas9) knock-in mice. Results: YAP and TAZ were up-regulated in murine and human HCC, but only deletion of TAZ consistently decreased HCC growth and mortality. Conversely, overexpression of activated TAZ was sufficient to trigger HCC. TAZ expression in HCC was regulated by cholesterol synthesis, as demonstrated by pharmacologic or genetic inhibition of 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCR), farnesyl pyrophosphate synthase, farnesyl-diphosphate farnesyltransferase 1 (FDFT1), or sterol regulatory element-binding protein 2 (SREBP2). TAZ- and MET/CTNNB1-S45Y–driven HCC required the expression of TEAD2 and, to a lesser extent, TEAD4. Accordingly, TEAD2 displayed the most profound effect on survival in patients with HCC. TAZ and TEAD2 promoted HCC via increased tumor cell proliferation, mediated by TAZ target genes ANLN and kinesin family member 23 (KIF23). Therapeutic targeting of HCC, using pan-TEAD inhibitors or the combination of a statin with sorafenib or anti–programmed cell death protein 1, decreased tumor growth. Conclusions: Our results suggest the cholesterol-TAZ-TEAD2-ANLN/KIF23 pathway as a mediator of HCC proliferation and tumor cell-intrinsic therapeutic target that could be synergistically combined with TIME-targeted therapies.

  • Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease

    Wang Z, Zhu S, Jia Y, Wang Y, Kubota N, Fujiwara N, Gordillo R, Lewis C, Zhu M, Sharma T, Li L, Zeng Q, Lin Y.H, Hsieh M.H, Gopal P, Wang T, Hoare M, Campbell P, Hoshida Y, Zhu H

    Cell (Cell)  186 ( 9 ) 1968 - 1984.e20 2023.04

    ISSN  00928674

    　View Summary

    Somatic mutations in nonmalignant tissues accumulate with age and injury, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate genes in human metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to nonalcoholic steatohepatitis (NASH). Proof-of-concept studies with mosaic loss of Mboat7, a membrane lipid acyltransferase, showed that increased steatosis accelerated clonal disappearance. Next, we induced pooled mosaicism in 63 known NASH genes, allowing us to trace mutant clones side by side. This in vivo tracing platform, which we coined MOSAICS, selected for mutations that ameliorate lipotoxicity, including mutant genes identified in human NASH. To prioritize new genes, additional screening of 472 candidates identified 23 somatic perturbations that promoted clonal expansion. In validation studies, liver-wide deletion of Tbx3, Bcl6, or Smyd2 resulted in protection against hepatic steatosis. Selection for clonal fitness in mouse and human livers identifies pathways that regulate metabolic disease.

  • Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development

    Wang X, He Q, Zhou C, Xu Y, Liu D, Fujiwara N, Kubota N, Click A, Henderson P, Vancil J, Marquez C.A, Gunasekaran G, Schwartz M.E, Tabrizian P, Sarpel U, Fiel M.I, Diao Y, Sun B, Hoshida Y, Liang S, Zhong Z

    Immunity (Immunity)  56 ( 1 ) 58 - 77.e11 2023.01

    ISSN  10747613

    　View Summary

    Obesity-induced chronic liver inflammation is a hallmark of nonalcoholic steatohepatitis (NASH)—an aggressive form of nonalcoholic fatty liver disease. However, it remains unclear how such a low-grade, yet persistent, inflammation is sustained in the liver. Here, we show that the macrophage phagocytic receptor TREM2, induced by hepatocyte-derived sphingosine-1-phosphate, was required for efferocytosis of lipid-laden apoptotic hepatocytes and thereby maintained liver immune homeostasis. However, prolonged hypernutrition led to the production of proinflammatory cytokines TNF and IL-1β in the liver to induce TREM2 shedding through ADAM17-dependent proteolytic cleavage. Loss of TREM2 resulted in aberrant accumulation of dying hepatocytes, thereby further augmenting proinflammatory cytokine production. This ultimately precipitated a vicious cycle that licensed chronic inflammation to drive simple steatosis transition to NASH. Therefore, impaired macrophage efferocytosis is a previously unrecognized key pathogenic event that enables chronic liver inflammation in obesity. Blocking TREM2 cleavage to restore efferocytosis may represent an effective strategy to treat NASH.

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Reviews, Commentaries, etc. 【 Display / hide 】

  • Molecular and immune landscape of hepatocellular carcinoma to guide therapeutic decision making.

    Dhanasekaran R, Suzuki H, Lemaitre L, Kubota N, Hoshida Y

    Hepatology (Baltimore, Md.)  2023.06

    ISSN  0270-9139

    　View Summary

    Liver cancer, primarily hepatocellular carcinoma (HCC), exhibits highly heterogeneous histological and molecular aberrations across tumors and within individual tumor nodules. Such inter- and intra-tumor heterogeneity may lead to diversity in the natural history of disease progression and various clinical disparities across the patients. Recently developed multi-modality, single-cell, and spatial omics profiling technologies have enabled interrogation of the inter-/intra-tumor heterogeneity in the cancer cells as well as the tumor immune microenvironment. These features may influence the natural history and efficacy of emerging therapies targeting novel molecular and immune pathways, some of which had been deemed undruggable. Thus, comprehensive characterization of the heterogeneities at various levels may facilitate discovery of biomarkers that enable personalized and rational treatment decisions and optimize treatment efficacy while minimizing the risk of adverse effects. Such companion biomarkers will also refine HCC treatment algorithms across disease stages for cost-effective patient management by optimizing the allocation of limited medical resources. Despite this promise, the complexity of the inter-/intra-tumor heterogeneity and ever-expanding inventory of therapeutic agents and regimens have made clinical evaluation and translation of biomarkers increasingly challenging. To address this issue, novel clinical trial designs have been proposed and incorporated into recent studies. In this review, we discuss the latest findings in the molecular and immune landscape of HCC for their potential and utility as biomarkers, framework of evaluation and clinical application of predictive/prognostic biomarkers, and ongoing biomarker-guided therapeutic clinical trials. These new developments may revolutionize patient care and substantially impact the still dismal HCC mortality.

  • Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease.

    Cell  2023.04

    　View Summary

    Somatic mutations in nonmalignant tissues accumulate with age and injury, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate genes in human metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to nonalcoholic steatohepatitis (NASH). Proof-of-concept studies with mosaic loss of Mboat7, a membrane lipid acyltransferase, showed that increased steatosis accelerated clonal disappearance. Next, we induced pooled mosaicism in 63 known NASH genes, allowing us to trace mutant clones side by side. This in vivo tracing platform, which we coined MOSAICS, selected for mutations that ameliorate lipotoxicity, including mutant genes identified in human NASH. To prioritize new genes, additional screening of 472 candidates identified 23 somatic perturbations that promoted clonal expansion. In validation studies, liver-wide deletion of Tbx3, Bcl6, or Smyd2 resulted in protection against hepatic steatosis. Selection for clonal fitness in mouse and human livers identifies pathways that regulate metabolic disease.

  • Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease

    bioRxiv  2023.03

  • Transcriptome-Guided Design of Physiological Multilineage Liver Organoids

    Zhu S, Kubota N, Hoshida Y

    Trends in Genetics (Trends in Genetics)  37 ( 5 ) 403 - 404 2021.05

    ISSN  01689525

    　View Summary

    Despite several technical challenges, human induced pluripotent stem cell (hiPSC)-derived organoids enable biologically and clinically relevant functional study of physiology and disease. In a recent Cell Systems article, Velazquez et al. report a novel strategy to identify regulators of multilineage organoid maturation by reverse-engineering from the global transcriptome of human tissues.

  • 【肝・胆道系症候群(第3版)-その他の肝・胆道系疾患を含めて-肝臓編(下)】肝腫瘍　肝細胞腺腫

    久保田 直人, 尾島 英知, 坂元 亨宇

    日本臨床 ((株)日本臨床社)  別冊 ( 肝・胆道系症候群II ) 136 - 141 2021.02

    ISSN  0047-1852

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Presentations 【 Display / hide 】

  • 胆嚢原発の脱分化型脂肪肉腫の一例(会議録)

    上野 彰久, 尾島 英知, 眞杉 洋平, 大島 剛, 紅林 泰, 久保田 直人, 阿部 雄太, 北川 雄光, 大喜多 肇, 坂元 亨宇

    [Domestic presentation]  日本病理学会, 

    2018.04
    , 

    Poster presentation

  • 肝細胞癌において、組織学的・分子生物学的分類に加えて免疫微小環境を評価する意義について(会議録)

    紅林 泰, 医, 病理, 尾島 英知, 辻川 華子, 久保田 直人, 前原 純樹, 阿部 雄太, 北郷 実, 篠田 昌宏, 北川 雄光, 坂元 亨宇

    [Domestic presentation]  日本病理学会, 

    2018.04
    , 

    Oral presentation (general)

  • 肝細胞癌胆管内腫瘍進展を病理学的に考察する上で参考となる特殊な混合型肝癌の一例(会議録/症例報告)

    久保田 直人, 医学部病理学教室, 尾島 英知, 辻川 華子, 北郷 実, 阿部 雄太, 益田 悠貴, 松坂 陽至, 奥田 茂男, 篠田 昌宏, 北川 雄光, 坂元 亨宇

    [Domestic presentation]  日本肝臓学会西部会, 

    2017.11
    , 

    Oral presentation (general)

  • 切除不能肝内胆管癌に対するConversion surgeryを施行した2症例の画像所見と病理組織の検討(会議録/症例報告)

    益田 悠貴(慶応義塾大学 医学部外科学教室(一般・消化器外科)), 日比 泰造, 板野 理, 篠田 昌宏, 北郷 実, 八木 洋, 阿部 雄太, 皆川 卓也, 久保田 直人, 紅林 泰, 尾島 英知, 坂元 亨宇, 北川 雄光

    [Domestic presentation]  日本肝胆膵外科学会, 

    2016.06
    , 

    Oral presentation (general)

  • 肝転移を伴う進行胃癌に対してSOX(S-1/Oxaliplatin)療法が奏効し、根治手術をし得た1例(会議録/症例報告)

    前田 祐助, 医学部外科学教室, 一般, 消化器外科, 高橋 常浩, 松田 諭, 中村 理恵子, 和田 則仁, 川久保 博文, 宇賀村 文, 平田 賢郎, 久保田 直人, 亀山 香織, 竹内 裕也, 金井 隆典, 北川 雄光

    [Domestic presentation]  日本胃癌学会, 

    2016.03
    , 

    Poster presentation

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • 胆管癌のシングルセル遺伝子発現解析と形態解析に基づく腫瘍層別化と治療への応用

    2024.04
    -
    2027.03

    若手研究, Principal investigator

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Awards 【 Display / hide 】

  • 若手医師症例報告奨励賞

    2017.12, The Japan Society of Hepatology, 肝細胞癌胆管内腫瘍進展を病理学的に考察する上で参考となる特殊な混合型肝癌の一例

    Type of Award： Award from Japanese society, conference, symposium, etc.

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Courses Taught 【 Display / hide 】

  • DISEASES OF ORGAN SYSTEMS

    2020

  • GENERAL PATHOLOGY

    2020

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Courses Previously Taught 【 Display / hide 】

  • 病理学各論

    Keio University

    2018.04
    -
    2019.03
    , 

    Full academic year, Laboratory work/practical work/exercise, Outside own faculty (within Keio), 1h, 120people

  • 病理学総論

    Keio University

    2018.04
    -
    2019.03
    , 

    Autumn Semester, Laboratory work/practical work/exercise, Outside own faculty (within Keio), 1h, 120people

  • 病理学総論

    慶應義塾大学医学部

    2018.04
    -
    2019.03

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Memberships in Academic Societies 【 Display / hide 】

  • The Japanese Society of Pathology, 

    2014.04
    -
    Present

  • The Japanese society of clinical cytology

    　

  • The Japanese Society of Hepatology

    　

  • Liver Cancer Study Group of Japan

    　
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