KEIO RESEARCHERS INFORMATION SYSTEM

Academic Background 【 Display / hide 】

Academic Background 【 Display / hide 】

• 2016.02

  University of Tsukuba, 人間総合科学研究科 疾患制御医学専攻

  Graduate School, Completed, Doctoral course

Academic Degrees 【 Display / hide 】

Academic Degrees 【 Display / hide 】

• 博士（医学）, University of Tsukuba, Dissertation, 2016.02

Papers 【 Display / hide 】

Papers 【 Display / hide 】

• An organoid library of human esophageal squamous cell carcinomas (ESCCs) uncovers the chemotherapy-resistant ESCC features.

  Nakagawa S, Sato T, Ohashi E, Kajita M, Miya F, Yamamoto K, Yotsumata H, Yamaguchi K, Nakajima Y, Miura A, Kinugasa Y, Ohteki T

  Communications biology 8 ( 1 ) 507 2025.04

  　View Summary

  Esophageal squamous cell carcinoma (ESCC) is a deadly cancer with a poor prognosis and a high recurrence rate after chemotherapy, posing a significant clinical challenge. To elucidate the molecular basis of chemotherapy (chemo)-resistance and to develop methods to effectively eliminate chemo-resistant tumor clones, we established an ESCC organoid (ESCCO) library from 24 ESCC patients of various stages, ages, and treatments. These ESCCOs faithfully recapitulate the oncogenic mutations observed in the original ESCC tissues and manifest tumorigenic properties when xenografted. The ESCCOs respond differently to cisplatin and 5-fluorouracil, chemotherapeutic agents commonly used to treat ESCC patients, with 7 ESCCOs exhibiting potent chemo-resistance. Notably, the chemo-resistant ESCCOs show higher genes involved in antioxidant stress response pathways and more accessible chromatin at their loci than the sensitive ESCCOs. These genes can serve as valuable biomarkers to stratify chemo-resistant ESCCs in histopathological specimens. Through drug screening using the ESCCO library, we reveal that fedratinib effectively induces cell death in chemo-resistant ESCCOs. Collectively, our human ESCCO model offers novel insights into the mechanism of chemo-resistance in ESCCs, which is critical for developing effective therapeutic approaches to eradicate the recurrence of ESCCs.

  • Access to Document (DOI)

• Effective calcineurin inhibitor treatment in adult-onset steroid-resistant nephrotic syndrome with a novel splice donor site variant of TRPC6: a case report.

  Nagasaka T, Uchiyama K, Hama EY, Kojima D, Kaneko K, Yoshimoto N, Yasuda I, Yamada M, Miya F, Suzuki H, Tajima T, Yamaguchi S, Hayashi K, Kanda T, Hashiguchi A, Kosaki K, Itoh H

  CEN case reports 14 ( 2 ) 208 - 216 2025.04

  　View Summary

  Transient receptor potential canonical 6 (TRPC6) variants, which were initially detected in adult-onset familial focal segmental glomerulosclerosis (FSGS), were also identified in pediatric-onset one. Here, we present a patient with adult-onset steroid-resistant nephrotic syndrome (SRNS) who harbored a likely pathogenic TRPC6 variant and partially responded to calcineurin inhibitors (CNIs). A 44-year-old woman with stable rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome was presented with nephrotic syndrome. Her renal biopsy results showed minor glomerular abnormalities. Upon admission, she was treated with steroids for around 4 weeks, but it was ineffective. After 1–2 weeks of cyclosporine A (CyA) administration, urine output increased, renal function improved without a decrease in proteinuria, and she was discharged. Her renal function was maintained for 2 months, but after a CyA dose reduction, she was again admitted to the hospital due to relapsing edema, decreased urine output, and worsening renal function. CyA was replaced by tacrolimus (TAC). A second renal biopsy showed nearly the same findings as the first except for tubulointerstitial lesions. After 1–2 weeks of TAC administration, urine output increased, and renal function improved. However, urinary protein levels did not decrease as before. After discharge, a whole exome analysis revealed a heterozygous splice donor site variant NM_004621.6;c.2644 + 1G > A in TRPC6. Genetic testing identified a novel splice donor site variant of TRPC6 in a patient with adult-onset SRNS, which prevented unnecessary steroid continuation. The safety and efficacy of CNI in TRPC6 glomerulopathy must be evaluated in future larger studies with longer follow-up.

  • Access to Document (DOI)

• BED-Craft for nanopore adaptive sampling: a tool for generating bed files with gene names as input data for enrichment sequencing.

  Miya F, Kosaki K

  BMC research notes 18 ( 1 ) 79 2025.02

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  Objective: Adaptive sampling, a nanopore sequencing method that enriches regions of interest (ROI), is cost-effective and useful. However, the process of defining targeted regions and creating the corresponding definition file (.bed file) are time-consuming and laborious. To simplify this process, we have developed a tool to easily create a.bed file for adaptive sampling directly from gene names. Results: The tool is freely available on GitHub at https://github.com/medicalbioinfo/BED-Craft. The input is a text file containing one or more gene names (symbols), and even with a large number of input genes (e.g., thousands), the resulting.bed file is generated in less than a second. The length of the buffer region added upstream and downstream of the ROI is designed to account for genome strand orientation, ensuring efficient adaptive sampling. The buffer length can also be modified by the user. The tool supports the genomes of human hg19, hg38, T2T-CHM13, and other species. For researchers unfamiliar with command-line input, a GUI version of the tool is also available at https://keio-cmg.jp/BED-Craft/. This easy-to-use.bed file generation tool enables adaptive sampling by easily changing the target genes of interest in nanopore sequencing, and provide great benefits to researchers and diagnostic laboratories.

  • Access to Document (DOI)

• Gene-based Hardy-Weinberg equilibrium test using genotype count data: application to six types of cancers.

  Nishino J, Miya F, Kato M

  BMC genomics 26 ( 1 ) 124 2025.02

  　View Summary

  Background: An alternative approach to investigate associations between genetic variants and disease is to examine deviations from the Hardy–Weinberg equilibrium (HWE) in genotype frequencies within a case population, instead of case–control association analysis. The HWE analysis requires disease cases and demonstrates a notable ability in mapping recessive variants. Allelic heterogeneity is a common phenomenon in diseases. While gene-based case–control association analysis successfully incorporates this heterogeneity, there are no such approaches for HWE analysis. Therefore, we proposed a gene-based HWE test (gene-HWT) by aggregating single-nucleotide polymorphism (SNP)-level HWE test statistics in a gene to address allelic heterogeneity. Results: This method used only genotype count data and publicly available linkage disequilibrium information and has a very low computational cost. Extensive simulations demonstrated that gene-HWT effectively controls the type I error at a low significance level and outperforms SNP-level HWE test in power when there are multiple causal variants within a gene. Using gene-HWT, we analyzed genotype count data from a genome-wide association study of six cancer types in Japanese individuals and suggest DGKE and ANO3 as potential germline factors in colorectal cancer. Furthermore, FSTL4 was suggested through a combined analysis across the six cancer types, with particularly notable associations observed in colorectal and prostate cancers. Conclusions: These findings indicate the potential of gene-HWT to elucidate the genetic basis of complex diseases, including cancer.

  • Access to Document (DOI)

• Comparative analysis of tongue cancer organoids among patients identifies the heritable nature of minimal residual disease.

  Sase M, Sato T, Sato H, Miya F, Zhang S, Haeno H, Kajita M, Noguchi T, Mori Y, Ohteki T

  Developmental cell 60 ( 3 ) 396 - 413.e6 2025.02

  ISSN  1534-5807

  　View Summary

  The relapse of tongue cancer (TC) after chemotherapy is caused by minimal residual disease (MRD), which is a few remaining cancer cells after chemotherapy. To understand the mechanism of MRD in TC, we created a library of TC organoids (TCOs) from 28 untreated TC patients at diverse ages and cancer stages. These TCOs reproduced the primary TC tissues both in vitro and in a xenograft model, and several TCO lines survived after cisplatin treatment (chemo-resistant TCOs). Of note, the chemo-resistant TCOs showed “heritable” embryonic diapause-like features before treatment and activation of the autophagy and cholesterol biosynthetic pathways. Importantly, inhibiting these pathways with specific inhibitors converted the chemo-resistant TCOs into chemo-sensitive TCOs. Conversely, autophagy activation with mTOR inhibitors conferred chemo-resistance on the chemo-sensitive TCOs. This unique model provides insights into the mechanism of MRD formation in TCs, leading to effective therapeutic approaches to reduce the recurrence of TC.

  • Access to Document (DOI)

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Reviews, Commentaries, etc. 【 Display / hide 】

Reviews, Commentaries, etc. 【 Display / hide 】

• 薬剤抵抗性で重篤な経過をたどったGNAO1遺伝子の新規突然変異による発達性てんかん性脳症の女児例

  小林 良行, 立石 裕一, 出雲 大幹, 江口 勇太, 宮 冬樹, 加藤 光広, 岡田 賢

  てんかん研究 ((一社)日本てんかん学会)  42 ( 2 ) 462 - 462 2024.09

  ISSN  0912-0890

• FGF12変異による新生児てんかんの1例

  松本 浩, 浅野 茉莉香, 大滝 里美, 寺西 宏美, 颯佐 かおり, 加藤 光広, 宮 冬樹, 山内 秀雄

  てんかん研究 ((一社)日本てんかん学会)  42 ( 2 ) 501 - 501 2024.09

  ISSN  0912-0890

• ATP1A3遺伝子の病的バリアントによる発達性てんかん性脳症の1例

  大滝 里美, 寺西 宏美, 颯佐 かおり, 田中 萌子, 堀田 奈緒美, 櫻井 隼人, 筧 紘子, 本多 正和, 國方 徹也, 加藤 光広, 宮 冬樹, 松本 浩, 山内 秀雄

  てんかん研究 ((一社)日本てんかん学会)  42 ( 2 ) 463 - 463 2024.09

  ISSN  0912-0890

• 遺伝子変異が判明した乳児期発症けいれん5例の検討

  大滝 里美, 寺西 宏美, 颯佐 かおり, 松本 浩, 宮 冬樹, 加藤 光広, 山内 秀雄

  脳と発達 ((一社)日本小児神経学会)  56 ( Suppl. ) S262 - S262 2024.05

  ISSN  0029-0831

• 脳室周囲結節状異所性灰白質を認めたSCN2A異常症による早期乳児発達性てんかん性脳症の一例

  前田 謙一, 森 こずえ, 日高 倫子, 木許 恭宏, 池田 俊郎, 宮 冬樹, 加藤 光広, 盛武 浩

  脳と発達 ((一社)日本小児神経学会)  56 ( Suppl. ) S313 - S313 2024.05

  ISSN  0029-0831

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

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

• Exploration of longevity-related factors using blood somatic mutation and genomic association analysis in centenarians

  2024.04

  -

  2027.03

  Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

  　View Summary

  血液中ではクローン性造血（CHIP）と呼ばれる特定の遺伝子の体細胞変異が選択的に増殖しクローン化している場合がある。CHIP保有者はがんや心血管疾患のリスクが高いことが知られている。CHIPの保有率は年齢依存性に上昇し、70歳では10％を超える。
  我々は百寿者（100歳以上）の全ゲノムシーケンスを進める過程で、超長寿者（110歳以上）では年齢依存的な予想よりもCHIP保有率が低いことを見出した。
  本研究は、CHIPの発生抑制と極端な長寿との間に関係があるとの仮説に基づき、約530名の百寿者について、80歳までの日本人（約7800人）とCHIPやゲノムの比較解析を行い、長寿関連因子の同定を目指す。

• 深層学習モデルで解き明かす発達性てんかん性脳症と脳形成異常の遺伝素因と画像診断

  2024.04

  -

  2027.03

  Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), No Setting

  　View Summary

  脳形成異常とてんかん性脳症で全エクソーム解析を行い、多数の原因遺伝子を明らかにしたが、全ゲノム解析でも約40%は原因が分からず、新たな発想による解析法の開発が必要である。人工知能(AI)の深層学習モデルによる解析が急速に進歩しており、希少疾患でありながら多数の検体と画像の集積がある優位性を生かして、AIによる遺伝子解析とMRI画像解析を連携させた解析を行う。モザイクもしくは反復配列の挿入が隠れた原因と仮説を立て、AIによる変異検出と検証、AI画像診断による原因遺伝子予測法の開発を行う。

• Combining Artificial Intelligence and RNA-Seq to elucidate new etiologies of genetic neurological disorders in childhood.

  2020.04

  -

  2024.03

  Grants-in-Aid for Scientific Research, Kato Mitsuhiro, Grant-in-Aid for Scientific Research (C), No Setting

  　View Summary

  Rare and intractable neurological diseases with childhood onset are highly heritable. However, even with whole genome sequencing, the causative gene identification rate is around 60%. New analysis methods need to be developed. Using SpliceAI, a splice site prediction algorithm based on artificial intelligence (AI) technology, we detected variants that had not been detected by conventional splice site prediction algorithms. An expression study of the variants using LCL showed aberrant transcripts suggesting splice abnormalities. Exome data of 488 samples from the probands and their families were analyzed using SpliceAI. Seven pathogenic splicing variants were identified. We confirmed the usefulness of AI in detecting new genetic etiologies.

• 脳オルガノイドを用いた巨脳症発症メカニズムの解明

  2020.04

  -

  2024.03

  日本学術振興会（科研費）, 基盤研究(B) , Research grant, Coinvestigator(s)

• 人工知能 (AI) とRNA-Seqの融合による遺伝性小児神経疾患の新たな病態解明

  2020.04

  -

  2023.03

  日本学術振興会（科研費）, 基盤研究(C) , Research grant, Coinvestigator(s)

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