Comprehensive understanding of spatio-temporal effects of mutant IDH1 during the development of cartilage forming tumors
Project/Area Number |
18H02929
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Basic Section 56020:Orthopedics-related
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Research Institution | Kyoto University |
Principal Investigator |
Toguchida Junya 京都大学, ウイルス・再生医科学研究所, 教授 (40273502)
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Co-Investigator(Kenkyū-buntansha) |
吉富 啓之 京都大学, 医学研究科, 准教授 (50402920)
金 永輝 京都大学, ウイルス・再生医科学研究所, 助教 (90620344)
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Project Period (FY) |
2018-04-01 – 2021-03-31
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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
Fiscal Year 2020: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
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Keywords | 軟骨形成性腫瘍 / IDH1遺伝子 / iPS細胞 / 軟骨肉腫 / IDH遺伝子 |
Outline of Final Research Achievements |
The purpose of this study is to understand the role of IDH1 gene mutation in cartilage-forming tumors using human iPS cells. Human iPSCs containing drug-inducible mutant IDH1 gene were established, and the expression of mutant IDH1 was induced after the differentiation to mesenchymal stromal cells (MSC). We found that the amount of reactive oxygen species (ROS) was increased in MSC by mutant IDH1, which activated the DNA repair machinery. This further induced the up-regulation of p16 gene, which finally induced cellular senescence of MSC with IDH1 mutaion. Interestingly, this serial phenomenon was escaped by the culture under the hypoxic condition such as those in bone marrow, from which cartilage forming tumors developed. These results revealed a part of tumor developing process of cartilage forming tumors.
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Academic Significance and Societal Importance of the Research Achievements |
軟骨形成性腫瘍におけるドライバー変異であるIDH1遺伝子の変異は、内軟骨腫においても軟骨肉腫と同頻度、存在しており、その悪性化における役割は明かにされていない。今回の研究によって、これまで想定されていなかった変異IDH1が増殖を抑制する作用をもつこと、そしてその作用が軟骨形成性腫瘍の発生母地である骨髄内環境で抑制され、その結果ゲノム及びエピゲノムの変異が蓄積されることで悪性化へのプロセスが進むことが明かになった。この成果は軟骨形成性腫瘍の発生機構そしてIDH1遺伝子の変異との関係を理解する上で意義ある成果であり、新規治療法の開発にも貢献するものであると考える。
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Report
(4 results)
Research Products
(29 results)
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[Journal Article] Differentiation of hypertrophic chondrocytes from human iPSCs for the in vitro modeling of chondrodysplasias2021
Author(s)
Pretemer Y, Kawai S, Nagata S, Nishio M, Watanabe M, Tamaki S, Alev C, Yamanaka Y, Xue JY, Wang Z, Fukiage K, Tsukanaka M, Futami T, Ikegawa S, Toguchida J
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Journal Title
Stem Cell Reports
Volume: 16
Issue: 3
Pages: 610-625
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Recapitulating the human segmentation clock with pluripotent stem cells2020
Author(s)
Matsuda M, Yamanaka Y, Uemura M, Osawa M, Saito MK, Nagahashi A, Nishio M, Guo L, Ikegawa S, Sakurai S, Kihara S, Maurissen TL, Nakamura M, Matsumoto T, Yoshitomi H, Ikeya M, Kawakami N, Yamamoto T, Woltjen K, Ebisuya M, Toguchida J, Alev C
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Journal Title
Nature
Volume: 580
Issue: 7801
Pages: 124-129
DOI
Related Report
Peer Reviewed
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[Journal Article] Clinical features and treatment outcome of desmoid-type fibromatosis: based on a bone and soft tissue tumor registry in Japan2019
Author(s)
Nishida Y, Kawai A, Toguchida J, Ogose A, Ae K, Kunisada T, Matsumoto Y, Matsunobu T, Takahashi K, Nishida K, Ozaki T
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Journal Title
Int J Clin Oncol
Volume: 24
Issue: 11
Pages: 1498-1505
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis.2018
Author(s)
Otomo N, Takeda K, Kawai S, Kou I, Guo L, Osawa M, Alev C, Kawakami N, Miyake N, Matsumoto N, Yasuhiko Y, Kotani T, Suzuki T, Uno K, Sudo H, Inami S, Taneichi H, Shigematsu H, Watanabe K, Yonezawa I, Sugawara R, Taniguchi Y, Minami S, Kaneko K, Nakamura M, Matsumoto M, Toguchida J, Watanabe K, Ikegawa S.
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Journal Title
Journal of Medical Genetics
Volume: -
Issue: 9
Pages: 622-628
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Human Sox4 facilitates the development of CXCL13-producing helper T cells in inflammatory environments.2018
Author(s)
Yoshitomi H, Kobayashi S, Miyagawa-Hayashino A, Okahata A, Doi K, Nishitani K, Murata K, Ito H, Tsuruyama T, Haga H, Matsuda S, Toguchida J
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Journal Title
Nature Communications
Volume: 9
Issue: 1
Pages: 3762-3762
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Prospective comparison of various radiological response criteria and pathological response to preoperative chemotherapy and survival in operable high-grade soft tissue sarcomas in the Japan Clinical Oncology Group study JCOG03042018
Author(s)
Tanaka K, Ogawa G, Mizusawa J, Naka N, Kawai A, Takahashi M, Hiruma T, Matsumoto Y, Tsuchiya H, Nakayama R, Hatano H, Emori M, Hosaka M, Yoshida Y, Toguchida J, Abe S, Asanuma K, Yokoyama R, Hiraga H, Yonemoto T, Morii T, Matsumoto S, Nagano A, Yoshikawa H, Fukuda H, Ozaki T, Iwamoto Y.
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Journal Title
World Journal of Surgical Oncology
Volume: 16
Issue: 1
Pages: 160-160
DOI
Related Report
Peer Reviewed
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[Journal Article] Current state of therapeutic development for rare cancers in Japan, and proposals for improvement.2018
Author(s)
Kawai A, Goto T, Shibata T, Tani K, Mizutani S, Nishikawa A, Shibata T, Matsumoto S, Nagata K, Narukawa M, Matsui S, Ando M, Toguchida J, Monden M, Heike T, Kimura S, Ueda R.
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Journal Title
Cancer Sci.
Volume: 109
Issue: 5
Pages: 1731-1737
DOI
Related Report
Peer Reviewed / Open Access
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