Tanaka, Nobuyuki

写真a

Affiliation

School of Medicine, Department of Urology (Shinanomachi)

Position

Senior Assistant Professor (Non-tenured)/Assistant Professor (Non-tenured)

External Links

Academic Background 【 Display / hide

  • 1996.04
    -
    2003.03

    慶應義塾大学, 医学部

    Graduated

Academic Degrees 【 Display / hide

  • 医学博士, Keio University, 2015.02

 

Papers 【 Display / hide

  • Landscape of prognostic signatures and immunogenomics of the AXL/GAS6 axis in renal cell carcinoma.

    Hakozaki K, Tanaka N, Takamatsu K, Takahashi R, Yasumizu Y, Mikami S, Shinojima T, Kakimi K, Kamatani T, Miya F, Tsunoda T, Aimono E, Nishihara H, Mizuno R, Oya M

    British journal of cancer (British Journal of Cancer)   2021.10

    ISSN  0007-0920

     View Summary

    Background: Cabozantinib is an oral tyrosine kinase inhibitor in renal cell carcinoma (RCC), whose targets include oncogenic AXL and unique ligand GAS6. Critical gaps in basic knowledge need to be addressed to devise an exclusive biomarker and candidate when targeting the AXL/GAS6 axis. Methods: To clarify the effects of the AXL/GAS6 axis on RCC, we herein performed a large-scale immunogenomic analysis and single-cell counts including various metastatic organs and histological subtypes of RCC. We further applied genome-wide mutation analyses and methylation arrays. Results: Varying patterns of AXL and GAS6 expression were observed throughout primary RCC tumours and metastases. Scoring individual AXL/GAS6 levels in the tumour centre and invasive margin, namely, the AXL/GAS6 score, showed a good ability to predict the prognosis of clear cell RCC. Metastasis- and histological subtype-specific differences in the AXL/GAS6 score existed since lung metastasis and the papillary subtype were weakly related to the AXL/GAS6 axis. Cell-by-cell immunohistological assessments clarified an immunosuppressive environment in tumours with high AXL/GAS6 scores. Genomic alterations in the PI3K-mTOR pathway and DNA methylation profiling revealed distinct differences with the AXL/GAS6 score in ccRCC. Conclusion: The AXL/GAS6 scoring system could predict the outcome of prognosis and work as a robust biomarker for the immunogenomic state in RCC.

  • Multiplexed single-cell pathology reveals the association of CD8 T-cell heterogeneity with prognostic outcomes in renal cell carcinoma

    Murakami T., Tanaka N., Takamatsu K., Hakozaki K., Fukumoto K., Masuda T., Mikami S., Shinojima T., Kakimi K., Tsunoda T., Sawada K., Imamura T., Mizuno R., Oya M.

    Cancer Immunology, Immunotherapy (Cancer Immunology, Immunotherapy)  70 ( 10 ) 3001 - 3013 2021.10

    ISSN  03407004

     View Summary

    Despite the high sensitivity of renal cell carcinoma (RCC) to immunotherapy, RCC has been recognized as an unusual disease in which CD8+ T-cell infiltration into the tumor beds is related to a poor prognosis. To approach the inner landscape of immunobiology of RCC, we performed multiplexed seven-color immunohistochemistry (CD8, CD39, PD-1, Foxp3, PD-L1, and pan-cytokeratin AE1/AE3 with DAPI), which revealed the automated single-cell counts and calculations of individual cell-to-cell distances. In total, 186 subjects were included, in which CD39 was used as a marker for distinguishing tumor-specific (CD39+) and bystander (CD39−) T-cells. Our clear cell RCC cohort also revealed a poor prognosis if the tumor showed increased CD8+ T-cell infiltration. Intratumoral CD8+CD39+ T-cells as well as their exhausted CD8+CD39+PD-1+ T-cells in the central tumor areas enabled the subgrouping of patients according to malignancy. Analysis using specimens post-antiangiogenic treatment revealed a dramatic increase in proliferative Treg fraction Foxp3+PD-1+ cells, suggesting a potential mechanism of hyperprogressive disease after uses of anti-PD-1 antibody. Our cell-by-cell study platform provided spatial information on tumors, where bystander CD8+CD39− T-cells were dominant in the invasive margin areas. We uncovered a potential interaction between CD8+CD39+PD-1+ T-cells and Foxp3+PD-1+ Treg cells due to cell-to-cell proximity, forming a spatial niche more specialized in immunosuppression under PD-1 blockade. A paradigm shift to the immunosuppressive environment was more obvious in metastatic lesions; rather the infiltration of Foxp3+ and Foxp3+PD-1+ Treg cells was more pronounced. With this multiplexed single-cell pathology technique, we revealed further insight into the immunobiological standing of RCC.

  • Profiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy.

    Takamatsu K, Tanaka N, Hakozaki K, Takahashi R, Teranishi Y, Murakami T, Kufukihara R, Niwa N, Mikami S, Shinojima T, Sasaki T, Sato Y, Kume H, Ogawa S, Kakimi K, Kamatani T, Miya F, Tsunoda T, Aimono E, Nishihara H, Sawada K, Imamura T, Mizuno R, Oya M

    Nature communications (Nature Communications)  12 ( 1 ) 5547 2021.09

     View Summary

    A cutting edge therapy for future immuno-oncology is targeting a new series of inhibitory receptors (IRs): LAG-3, TIM-3, and TIGIT. Both immunogenomic analyses and diagnostic platforms to distinguish candidates and predict good responders to these IR-related agents are vital in clinical pathology. By applying an automated single-cell count for immunolabelled LAG-3, TIM-3, and TIGIT, we reveal that individual IR levels with exclusive domination in each tumour can serve as valid biomarkers for profiling human renal cell carcinoma (RCC). We uncover the immunogenomic landscape associated with individual IR levels in human RCC tumours with metastases in various organs and histological subtypes. We then externally validate our results and devise a workflow with optimal biomarker cut-offs for discriminating the LAG-3, TIM-3, and TIGIT tumour profiles. The discrimination of LAG-3, TIM-3, and TIGIT profiles in tumours may have a broad impact on investigations of immunotherapy responses after targeting a new series of IRs.

  • Germline whole-gene deletion of fh diagnosed from tumor profiling

    Ueki A., Sugano K., Misu K., Aimono E., Nakamura K., Tanishima S., Tanaka N., Mikami S., Hirasawa A., Ando M., Yoshida T., Oya M., Nishihara H., Kosaki K.

    International Journal of Molecular Sciences (International Journal of Molecular Sciences)  22 ( 15 )  2021.08

    ISSN  16616596

     View Summary

    Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical se-quencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient’s family was advised to undergo genetic counseling to consider additional RCC screening.

  • Risk factors for haemodynamic instability and its prolongation during laparoscopic adrenalectomy for pheochromocytoma.

    Takeda T, Hakozaki K, Yanai Y, Masuda T, Yasumizu Y, Tanaka N, Matsumoto K, Morita S, Kosaka T, Mizuno R, Kurihara I, Asanuma H, Itoh H, Oya M

    Clinical endocrinology (Clinical Endocrinology)  95 ( 5 ) 716 - 726 2021.07

    ISSN  0300-0664

     View Summary

    Objective: Pheochromocytoma is a rare neuroendocrine tumour that secretes catecholamines and originates in the adrenal gland. Although surgical resection is the only curative therapy for pheochromocytoma, it is associated with a risk of haemodynamic instability (HDI), such as extremely high blood pressure and/or post tumour removal hypotension and shock. We investigated the risk factors for HDI during pheochromocytoma surgery. Design and Patients: Eighty-two patients who underwent laparoscopic adrenalectomy for pheochromocytoma between July 2002 and February 2020 were examined. We excluded 3 patients with bilateral disease and 11 without detailed 24 h urinary data. We defined HDI as systolic blood pressure ≥ 200 or <80 mmHg. We investigated the risk factors for HDI during laparoscopic adrenalectomy for pheochromocytoma. Results: There were 29 males and 39 females with a median age of 50.5 years. Tumours were localised on the right adrenal gland in 28 patients and on the left in 40. The median tumour diameter was 37.5 mm and the median pneumoperitoneum time was 93.5 min. Twenty-five out of sixty-eight patients (37%) developed HDI. A multivariate analysis identified diabetes mellitus (DM; odds ratio: 3.834; 95% confidence interval: 1.062–13.83; p =.04) as an independent predictor of HDI. In terms of hormonal data, median 24 h urinary epinephrine levels (p =.04) and metanephrine levels (p =.01) were significantly higher in the HDI group. DM was also considered as a risk factor for prolonged HDI (p =.02). Conclusion: Surgeons and anaesthesiologists need to be aware of the risk of HDI and its prolongation during laparoscopic adrenalectomy for pheochromocytoma for DM patients.

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Reviews, Commentaries, etc. 【 Display / hide

  • 前立腺全摘後の生化学的再発に対する、救済放射線治療と救済内分泌治療の予後比較

    松本 一宏, 丹羽 直也, 萩原 正幸, 小坂 威雄, 武田 利和, 田中 伸之, 森田 伸也, 水野 隆一, 篠島 利明, 原 智, 浅沼 宏, 大家 基嗣

    泌尿器外科 (医学図書出版(株))  34 ( 臨増 ) 802 - 802 2021.06

    ISSN  0914-6180

  • 腎細胞癌との鑑別が困難であった腎静脈内腫瘍栓を伴う腎原発びまん性大細胞性B細胞リンパ腫の1例

    西元 ゆい, 松本 一宏, 馬場 優人, 秋田 大宇, 三上 修治, 安水 洋太, 田中 伸之, 武田 利和, 森田 伸也, 小坂 威雄, 水野 隆一, 浅沼 宏, 陣崎 雅弘, 大家 基嗣

    泌尿器外科 (医学図書出版(株))  34 ( 臨増 ) 778 - 778 2021.06

    ISSN  0914-6180

  • 術前画像診断が困難であったアルドステロン産生微小腺腫の後方視的検討

    桝田 司, 武田 利和, 秋田 大宇, 栗原 勲, 安水 洋太, 田中 伸之, 松本 一宏, 森田 伸也, 小坂 威雄, 水野 隆一, 浅沼 宏, 陣崎 雅弘, 伊藤 裕, 大家 基嗣

    泌尿器外科 (医学図書出版(株))  34 ( 臨増 ) 776 - 776 2021.06

    ISSN  0914-6180

  • 本邦尿路上皮癌のマイクロサテライト不安定性調査とリンチ症候群スクリーニングの試み

    田中 伸之, 大家 基嗣, 水野 隆一, 三上 修治

    大和証券ヘルス財団研究業績集 ((公財)大和証券ヘルス財団)   ( 44 ) 62 - 65 2021.03

  • 21水酸化酵素欠損症に巨大な両側副腎骨髄脂肪腫を合併した一例

    松林 秀幸, 武田 利和, 馬場 優人, 桝田 司, 安水 洋太, 田中 伸之, 松本 一宏, 森田 伸也, 小坂 威雄, 水野 隆一, 浅沼 宏, 大家 基嗣

    泌尿器外科 (医学図書出版(株))  34 ( 2 ) 210 - 210 2021.02

    ISSN  0914-6180

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Presentations 【 Display / hide

  • Single-cell RNA-seq analysis of intra-tumor heterogeneity dynamics reveals the novel platinum resistance gene COX7B in patients with urinary bladder cancer

    第108回日本泌尿器科学会総会, 2020.12

  • 多様化する前立腺肥大症患者と接触式レーザー前立腺蒸散術の可能性

    LASER WEEK IN KOCHI, 2020.10, Symposium, Workshop, Panelist (nomination)

  • 高齢者における接触式レーザー前立腺蒸散術の治療成績:核出術との比較検討

    第27回日本排尿機能学会, 2020.10

  • 3次元ライトシート顕微鏡による腫瘍内不均一性の可視化:スライドフリーな1細胞レベルのタンパク/RNA発現解析

    第78回日本癌学会学術総会, 2019.09, Symposium, Workshop, Panelist (public offering)

  • 3次元ライトシート顕微鏡による泌尿器癌微小環境の可視化: 組織透明化の新規プロトコールと臨床応用

    第107回日本泌尿器科学会総会, 2019.04

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

  • がん多様性をin situで見える化する解析プラットフォーム構築と臨床応用

    2021.07
    -
    2024.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 田中 伸之, 挑戦的研究(萌芽)

  • 腎癌幹細胞ニッチを掌握する解析基盤の構築とがん組織不均一性の理解

    2019.04
    -
    2022.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 田中 伸之, 基盤研究(B), Principal Investigator

  • 腫瘍内不均一性を可視化する次世代癌イメージングを用いた薬剤感受性の予測モデル構築

    2018.06
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 田中 伸之, Grant-in-Aid for Challenging Research (Exploratory) , Principal Investigator

  • 腎細胞癌の免疫環境と血管新生阻害後のリモデリングの統合的解析による新規治療の開発

    2018.04
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 大家 基嗣, 基盤研究(B), Co-investigator

  • シングルセルレベルの腫瘍内不均一性をターゲットとする革新的な創薬研究

    2018.04
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 田中 伸之, Grant-in-Aid for Scientific Research on Innovative Areas, Principal Investigator

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Awards 【 Display / hide

  • 第30回日本泌尿器科学会研究助成金

    2021

  • 公益財団法人SGH財団SGHがん研究助成

    2020

  • 公益財団法人小林がん学術振興会特別萌芽的研究継続助成

    2020

  • 第108回日本泌尿器科学会総会、International Session Award 部門(Urothelial Tumors)

    2020

  • 公益財団法人大和証券ヘルス財団調査研究助成

    2019

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Courses Taught 【 Display / hide

  • LECTURE SERIES, UROLOGY

    2021

  • LECTURE SERIES, UROLOGY

    2020

  • LECTURE SERIES, UROLOGY

    2019