Physical Biomarkers Based on Dynamics of Cancer Cells and Organoids

• Project/Area Number: 20H00661
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 90:Biomedical engineering and related fields
• Research Institution: Kyoto University
• Principal Investigator: Tanaka Motomu 京都大学, 高等研究院, 特任教授 (00706814)
• Co-Investigator(Kenkyū-buntansha): 妹尾 浩 京都大学, 医学研究科, 教授 (90335266)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥44,980,000 (Direct Cost: ¥34,600,000、Indirect Cost: ¥10,380,000); Fiscal Year 2022: ¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000); Fiscal Year 2021: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000); Fiscal Year 2020: ¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000)
• Keywords: バイオマーカー / 消化器がん / 臨床ヒト試料 / 時空間ダイナミクス / オルガノイド / 数理モデル / 機械学習 / 定量的バイオマーカー

Outline of Research at the Start

本研究は、遺伝子レベルの変異ががん細胞やその集団の動態に与える影響をマルチスケールで定量解析し、これを基盤としたがん診断の新たなバイオマーカーの創出を目指す。具体的には、遺伝子変異が特定されたヒト大腸がん細胞などを用いて(1) 単一細胞レベルの変形と運動(2) 細胞集団レベルの大規模変形と形態形成といった異なる階層構造のダイナミクスの精密計測と数理解析を行う。
研究分担者・妹尾の全面協力のもと、検体由来の細胞など臨床に密接したサンプル解析によって得られた「がん細胞遊走の持続時間」「スフェロイドの大規模変形によるエネルギー散逸量」などの定量データを駆使して、新たながん診断の定量標準を開拓する。

Outline of Final Research Achievements

The primary aim of this research is to establish a new “quantitative biomarker for cancer diagnosis” by using the multiscale numerical analysis, ranging from (1) self-propelled deformation and motion of mouse pancreatic cancer cells with defined genetic mutation to (2) large-scale deformation of patient-derived colorectal cancer organoids. This work was performed under tight collaboration with Department of Gastroenterology,, Kyoto University Hospital, headed by Prof. H. Seno.
On the single cell level, the data obtained from the systematic loss of function analysis indicated that the numerical analysis of single cell dynamics can be used to detect the distinct gene mutations. On the organoid level, we have successfully identified 2-3 indices for the potential detection of the metastatic capacity of the patient-derived organoids.

Academic Significance and Societal Importance of the Research Achievements

本研究で提唱する「通常の表現型では識別できない遺伝子変異を動態解析で数値化する」というアプローチは、現在広く用いられている『患者由来オルガノイドの網羅的遺伝子解析』や『固定染色した単一細胞の画像解析による特徴的な表現型の抽出』とは一線を画し『生きた細胞や組織の自発的な変形や運動』の数値化に主眼を置いた、独自性が高くかつ相補的な手法である。
さらに本研究を推進する中で、この手法を乳がん・急性骨髄性白血病・老化といったテーマへ発展・展開させた実例を論文として発表するなど、当初予期していなかったような成果をあげることができた。

Research Products

• [Int'l Joint Research] 欧州分子生物学研究所（EMBL)(ドイツ)
• [Int'l Joint Research] ハイデルベルク大学 医学部、物理学部(ドイツ)
• [Int'l Joint Research] 国立がん研究所（DKFZ）(ドイツ)
• [Int'l Joint Research] 欧州分子生物学研究所（EMBL)(ドイツ)
• [Int'l Joint Research] ハイデルベルク大学 医学部(ドイツ)
• [Int'l Joint Research] 国立がん研究所 (DKFZ)(ドイツ)
• [Int'l Joint Research] 欧州分子生物学研究所/ミュンヘン工科大学(ドイツ)
• [Journal Article] Wnt/β-catenin signaling induces axial elasticity patterns of Hydra extracellular matrix (2023)
  • Author(s): Veschgini Mariam、Suzuki Ryo、Kling Svenja、Petersen Hendrik O.、Bergheim Bruno Gideon、Abuillan Wasim、Linke Philipp、Kaufmann Stefan、Burghammer Manfred、Engel Ulrike、Stein Frank、?zbek Suat、Holstein Thomas W.、Tanaka Motomu
  • Journal Title: iScience Volume: 26 Issue: 4 Pages: 106416-106416
  • DOI: 10.1016/j.isci.2023.106416
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Discreteness of cell?surface contacts affects spatio-temporal dynamics, adhesion, and proliferation of mouse embryonic stem cells (2022)
  • Author(s): Kimmle Esther、Hajian Foroushani Zahra、Keppler Stephan、Thoma Judith、Hayashi Kentaro、Yamamoto Akihisa、Bastmeyer Martin、Tanaka Motomu
  • Journal Title: Frontiers in Physics Volume: 10 Pages: 1-13
  • DOI: 10.3389/fphy.2022.1052106
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Stimulus-Responsive, Gelatin-Containing Supramolecular Nanofibers as Switchable 3D Microenvironments for Cells (2022)
  • Author(s): Hayashi Kentaro、Matsuda Mami、Nakahata Masaki、Takashima Yoshinori、Tanaka Motomu
  • Journal Title: Polymers Volume: 14 Issue: 20 Pages: 4407-4407
  • DOI: 10.3390/polym14204407
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] One-Step Synthesis of Gelatin-Conjugated Supramolecular Hydrogels for Dynamic Regulation of Adhesion Contact and Morphology of Myoblasts (2022)
  • Author(s): Hayashi Kentaro、Matsuda Mami、Mitake Nodoka、Nakahata Masaki、Munding Natalie、Harada Akira、Kaufmann Stefan、Takashima Yoshinori、Tanaka Motomu
  • Journal Title: ACS Applied Polymer Materials Volume: 4 Issue: 4 Pages: 2595-2603
  • DOI: 10.1021/acsapm.1c01902
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glucose Metabolism and Aging of Hematopoietic Stem and Progenitor Cells (2022)
  • Author(s): Poisa-Beiro Laura、Landry Jonathan J. M.、Raffel Simon、Tanaka Motomu、Zaugg Judith、Gavin Anne-Claude、Ho Anthony D.
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 6 Pages: 3028-3028
  • DOI: 10.3390/ijms23063028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia (2022)
  • Author(s): He, L.; Arnold, C.; Thoma, J.; Rohde, C.; Kholmatov, M.; Garg, S.; Hsiao, C.; Viol, L.; Zhang, K.; Sun, R.; Schmidt, C.; Janssen, M.; MacRae, T.; Huber, K.; Thiede, C.; Hebert, J.; Sauvageau, G.; Spratte, J.; Fluhr, H.; Aust, G.; Mueller-Tidow, C. Niehrs, C.; Pereira, G.; Hamann, J.; Tanaka, M.; Zaugg, J.; & Pabst, C.
  • Journal Title: EMBO Molecular Medicine Volume: 14 Issue: 4
  • DOI: 10.15252/emmm.202114990
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Superiority of Mature Differentiated Cultured Human Corneal Endothelial Cell Injection Therapy for Corneal Endothelial Failure (2022)
  • Author(s): UENO MORIO、TODA MUNETOYO、NUMA KOHSAKU、TANAKA HIROSHI、IMAI KOJIRO、BUSH JOHN、TERAMUKAI SATOSHI、OKUMURA NAOKI、KOIZUMI NORIKO、YAMAMOTO AKIHISA、TANAKA MOTOMU、SOTOZONO CHIE、HAMURO JUNJI、KINOSHITA SHIGERU
  • Journal Title: American Journal of Ophthalmology Volume: 237 Pages: 267-277
  • DOI: 10.1016/j.ajo.2021.11.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of ASAP1 in the MMTV-PyMT model of luminal breast cancer activates AKT, accelerates tumorigenesis, and promotes metastasis (2022)
  • Author(s): Schreiber Caroline、Gruber Annette、Rosswag Sven、Saraswati Supriya、Harkins Shannon、Thiele Wilko、Foroushani Zahra Hajian、Munding Natalie、Schmaus Anja、Rothley Melanie、Dimmler Arno、Tanaka Motomu、Garvalov Boyan K.、Sleeman Jonathan P.
  • Journal Title: Cancer Letters Volume: 533 Pages: 215600-215600
  • DOI: 10.1016/j.canlet.2022.215600
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Elevated Central Carbon Metabolism - a Hallmark for Senescent Cells in Aging Human Hematopoietic Stem Cell Compartment (2021)
  • Author(s): Poisa-Beiro Laura、Landry Jonathan、Raffel Simon、Eckstein Volker、Gavin Anne-Claude、Tanaka Motomu、Benes Vladimir、Ho Anthony D.
  • Journal Title: Blood Volume: 138 Issue: Supplement 1 Pages: 1088-1088
  • DOI: 10.1182/blood-2021-150761
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Id1 and Id3 Are Regulated Through Matrix‐Assisted Autocrine BMP Signaling and Represent Therapeutic Targets in Melanoma (2021)
  • Author(s): Sedlmeier, G.; Al-Rawi, V.; Buchert, J.; Yserentant, K.; Rothley, M.; Steshina, A.; Graessle, S.; Wu, R. L.; Hurrle, T.; Richer, W.; Decraene, C.; Thiele, W.; Utikal, J.; Abuillan, W.; Tanaka, M.; Herten, D. P.; Hill, C. S.; Garvalov, B. K.; Jung, N.; Braese S. & Sleeman, J. P.
  • Journal Title: Advanced Therapeutics Volume: 4 Issue: 2 Pages: 2000065-2000065
  • DOI: 10.1002/adtp.202000065
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Extreme deformability of insect cell membranes is governed by phospholipid scrambling (2021)
  • Author(s): Shiomi A., Nagao K., Yokota N., Tsuchiya M., Kato U., Juni N., Hara Y., Mori M.X., Mori Y., Ui-Tei K., Murate M., Kobayashi T., Nishino Y., Miyazawa A., Yamamoto A., Suzuki R., Kaufmann S., Tanaka M., Tatsumi K., Nakabe K., Shintaku H., Yesylevsky S., Bogdanov M., Umeda M.
  • Journal Title: Cell Reports Volume: 35 Issue: 10 Pages: 109219-109219
  • DOI: 10.1016/j.celrep.2021.109219
  • NAID: 120007052731
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Critical role of lipid membranes in polarization and migration of cells: a biophysical view. (2021)
  • Author(s): Sackmann,E. & Tanaka, M.
  • Journal Title: Biophys Rev. Volume: 13 Issue: 1 Pages: 123-138
  • DOI: 10.1007/s12551-021-00781-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glycogen accumulation, central carbon metabolism, and aging of hematopoietic stem and progenitor cells (2020)
  • Author(s): Poisa-Beiro Laura、Thoma Judith、Landry Jonathan、Sauer Sven、Yamamoto Akihisa、Eckstein Volker、Romanov Natalie、Raffel Simon、Hoffmann Georg F.、Bork Peer、Benes Vladimir、Gavin Anne-Claude、Tanaka Motomu、Ho Anthony D.
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 1-11
  • DOI: 10.1038/s41598-020-68396-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Mechanical forces and Wnt signaling (2022)
  • Author(s): 田中 求
  • Organizer: Wnt signaling in development and diseases
  • Int'l Joint Research / Invited
• [Presentation] 界面から解き明かす生命現象のダイナミクス (2022)
  • Author(s): 田中 求
  • Organizer: 第73回コロイドおよび界面科学討論会
  • Int'l Joint Research / Invited
• [Presentation] Spatio-temporal analysis of infected cells reveals the protection of HbS carriers from severe malari (2022)
  • Author(s): 田中 求
  • Organizer: 第三回「医学と数理」研究会 京大-ハイデルベルク大-理研ワークショップ 発表年
  • Int'l Joint Research
• [Presentation] Physical Modeling of Cell Surfaces: Interfacial Forces and Mechanics (2021)
  • Author(s): 田中 求
  • Organizer: Neutrons in Life Science and Biomaterials Swedish Neutron Graduate School (SWEDNESS)サマーシンポジウム
  • Int'l Joint Research / Invited
• [Presentation] 界面から読み解く抗菌・殺菌の物理化学：感染症と向き合う社会に貢献する分析科学 (2021)
  • Author(s): 田中 求
  • Organizer: 大阪大学基礎工学研究科における次世代分析科学を考える会主催次世代分析化学へ向けてのセミナーシリーズ①
  • Invited
• [Presentation] Biological Interfaces out of Equilibrium - New Challenges in Soft Interface Science (2021)
  • Author(s): 田中 求
  • Organizer: Soft Interface Seminar九州大学・国際セミナーシリーズ
  • Int'l Joint Research / Invited
• [Presentation] Physics of Infectious Diseases (2021)
  • Author(s): 田中 求
  • Organizer: 日本生物物理学会
  • Invited
• [Presentation] ヒト角膜内皮再生医療における細胞品質・予後予測の統合的バイオマーカーの開発 (2020)
  • Author(s): 山本暁久, 田中 求
  • Organizer: 第69回高分子討論会
  • Invited
• [Presentation] 臨床医学の課題に切り込む数物科学 (2020)
  • Author(s): 田中 求
  • Organizer: 第12回コロキウム
  • Invited
• [Book] Receptor-Functionalized Lipid Membranes as Biomimetic Surfaces for Adhesion of Plasmodium falciparum-Infected Erythrocytes (2022)
  • Author(s): Tanaka M.;Lanzer M.
  • Total Pages: 796
  • Publisher: Springer Nature
• [Book] Cell-Inspired Materials and Engineering, Fundamental Biomedical Technologies (2021)
  • Author(s): Tanaka, M.; Yamamoto, A.
  • Total Pages: 257
  • Publisher: Springer
• [Funded Workshop] 京大－ハイデルベルク大－理研ワークショップ (2020)