Proposal of a Spatio-Temporal Inclusionary Mathematical Analysis Method for Single Cells to Understand Tumor Tissue Diversity

• Project/Area Number: 19K12215
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 62010:Life, health and medical informatics-related
• Research Institution: The University of Tokyo
• Principal Investigator: Katayama Kotoe 東京大学, 医科学研究所, 准教授 (40581195)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: がん / バイオインフォマティクス / 単一細胞解析 / シンボリックデータ / 接合分布関数 / 確率分布

Outline of Research at the Start

腫瘍ゲノム解析の分野では細胞集団としての平均的がん細胞の特徴抽出では説明できない腫瘍内細胞不均一性を解明することが大きな課題となっている。がんの発生及び進化は時間的にも空間的にも複雑なメカニズムを持ち、転移等の命に関わる事象について説明しうる有用な情報を抽出し解釈することで実際の医療や創薬につなげていくことが重要な課題である。本研究では単一細胞解析に内包される細胞周期や時空間情報を確率的変動として記述することにより腫瘍細胞多様性の起源と進化を数理的解析手法を用いて明らかにするものである。

Outline of Final Research Achievements

This study attempts to solve the problem that most of the current techniques for single cell analysis require the destruction of cells, and although it is possible to obtain cellular information at that point in time, the temporal and spatial information of the cells themselves is lost.
Since conventional methods treat multiple cells with different processes as a single population without distinction, they are limited in their ability to characterize phenomena such as cancer development mechanisms and metastasis. In addition, we constructed a model that clarifies the diversity of cancer cells in tumor tissue by describing fluctuations in the cell cycle of a single cell as a probability distribution.

Academic Significance and Societal Importance of the Research Achievements

単一細胞解析において細胞の破壊を必須としており、時間および空間情報が欠失する問題を数理的モデルを用いて解決しようとするものである。
腫瘍組織内のがん細胞の多様性が「腫瘍内不均一性」としてがんの発生には、突然変異した細胞のクローンに起因するプロセスと、がん幹細胞から分化したプロセスの両方が関与していると考えられている。これまでの手法では、複数個の細胞を区別のして扱うことができなかったがこれを数理的な観点から細胞周期による揺らぎを確率分布とすることで腫がん細胞の多様性を明らかとするモデルの構築を行った

Research Products

• [Journal Article] Early dynamics of circulating tumor DNA predict clinical response to immune checkpoint inhibitors in metastatic renal cell carcinoma (2022)
  • Author(s): Koh Yoko、Nakano Kosuke、Katayama Kotoe、Yamamichi Gaku、Yumiba Satoru、Tomiyama Eisuke、Matsushita Makoto、Hayashi Yujiro、Yamamoto Yoshiyuki、Kato Taigo、Hatano Koji、Kawashima Atsunari、Ujike Takeshi、Imamura Ryoichi、Yamaguchi Rui、Imoto Seiya、Shiotsu Yukimasa、Nonomura Norio、Uemura Motohide
  • Journal Title: International Journal of Urology Volume: 2 Issue: 5 Pages: 462-469
  • DOI: 10.1111/iju.14816
  • Peer Reviewed / Open Access
• [Journal Article] Perioperative circulating tumor DNA enables the identification of patients with poor prognosis in upper tract urothelial carcinoma (2022)
  • Author(s): Nakano K, Koh Y, Yamamichi G, Yumiba S, Tomiyama E, Matsushita M, Hayashi Y, Wang C, Ishizuya Y, Yamamoto Y, Kato T, Hatano K, Kawashima A, Ujike T, Fujita K, Kiyotani K, Katayama K, Yamaguchi R, Imoto S, Imamura R, Nonomura N, Uemura M
  • Journal Title: Cancer Science Volume: - Issue: 5 Pages: 1830-1842
  • DOI: 10.1111/cas.15334
  • Peer Reviewed
• [Journal Article] Clinical Characteristics of Patients with Coronavirus Disease (COVID-19): Preliminary Baseline Report of Japan COVID-19 Task Force, a Nationwide Consortium to Investigate Host Genetics of COVID-19 (2021)
  • Author(s): Tanaka, Hiromu, et al.
  • Journal Title: International Journal of Infectious Diseases Volume: 113 Pages: 74-81
  • DOI: 10.1016/j.ijid.2021.09.070
  • Peer Reviewed
• [Journal Article] Application of targeted nanopore sequencing for the screening and determination of structural variants in patients with Lynch syndrome (2021)
  • Author(s): Yamaguchi Kiyoshiら著者24名. Kazuo Tamura 16番目の著者
  • Journal Title: Journal of Human Genetics Volume: 66 Issue: 11 Pages: 1053-1060
  • DOI: 10.1038/s10038-021-00927-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional Restoration of Bacteriomes and Viromes by Fecal Microbiota Transplantation (2021)
  • Author(s): Fujimoto, Kosuke, et al.
  • Journal Title: Gastroenterology Volume: - Issue: 6 Pages: 400-405
  • DOI: 10.1053/j.gastro.2021.02.013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] COVID-19 risk assessment at the opening ceremony of the Tokyo 2020 Olympic Games (2021)
  • Author(s): Murakami Michio、Miura Fuminari、Kitajima Masaaki、Fujii Kenkichi、Yasutaka Tetsuo、Iwasaki Yuichi、Ono Kyoko、Shimazu Yuzo、Sorano Sumire、Okuda Tomoaki、Ozaki Akihiko、Katayama Kotoe、Nishikawa Yoshitaka、Kobashi Yurie、Sawano Toyoaki、Abe Toshiki、Saito Masaya M.、Tsubokura Masaharu、Naito Wataru、Imoto Seiya
  • Journal Title: Microbial Risk Analysis Volume: - Pages: 100162-100162
  • DOI: 10.1016/j.mran.2021.100162
  • Peer Reviewed / Open Access
• [Journal Article] Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo. (2020)
  • Author(s): Omori S, Wang TW, Johmura Y, ..., Sakamoto T (15番目), ..., Nakanishi M.
  • Journal Title: Cell Metab Volume: 32 Issue: 5 Pages: 814-828
  • DOI: 10.1016/j.cmet.2020.09.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations (2019)
  • Author(s): Tsuda Yusuke、Matsubara Daisuke (5th) etc
  • Journal Title: International Journal of Cancer Volume: 145 Issue: 12 Pages: 3276-3284
  • DOI: 10.1002/ijc.32421
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrated exome and RNA sequencing of dedifferentiated liposarcoma (2019)
  • Author(s): Hirata Makoto、Matsubara Daisuke (21th) etc
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s41467-019-13286-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Replication stress triggers microsatellite destabilization and hypermutation leading to clonal expansion in vitro (2019)
  • Author(s): Matsuno Yusuke、Atsumi Yuko、Shimizu Atsuhiro、Katayama Kotoe、Fujimori Haruka、Hyodo Mai、Minakawa Yusuke、Nakatsu Yoshimichi、Kaneko Syuzo、Hamamoto Ryuji、Shimamura Teppei、Miyano Satoru、Tsuzuki Teruhisa、Hanaoka Fumio、Yoshioka Ken-ichi
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 3925-3925
  • DOI: 10.1038/s41467-019-11760-2
  • Peer Reviewed / Open Access
• [Journal Article] Genomic Heterogeneity Within Individual Prostate Cancer Foci Impacts Predictive Biomarkers of Targeted Therapy (2018)
  • Author(s): VanderWeele DJ, Finney R, Katayama K, Gillard M, Paner G, Imoto S, Yamaguchi R, Wheeler D, Lack J, Cam M, Pontier A, Nguyen YTM, Maejima K, Sasaki-Oku A, Nakano K, Tanaka H, Vander Griend D, Kubo M, Ratain MJ, Miyano S, Nakagawa H
  • Journal Title: Eur Urol Focus Volume: pii: S2405-4569(18) Issue: 3 Pages: 30007-5
  • DOI: 10.1016/j.euf.2018.01.006
  • Peer Reviewed / Open Access / Int'l Joint Research