Investigation for the pathomechanism of cartilage-forming tumors by whole exome sequencing

• Project/Area Number: 24390353
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Kyoto University
• Principal Investigator: TOGUCHIDA Junya 京都大学, 再生医科学研究所, 教授 (40273502)
• Co-Investigator(Kenkyū-buntansha): KATO Tomohisa 京都大学, iPS細胞研究所, 特定研究員 (50301247) ; IKEYA Makoto 京都大学, iPS細胞研究所, 准教授 (20442923)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2014: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2012: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: 軟骨形成腫瘍 / Maffucci症候群 / iPS細胞 / Ollier病 / エクソーム解析

Outline of Final Research Achievements

To investigate the pathomechanism of cartilage-forming tumors, we have focused on one patient with Maffucci syndrome, in whom multiple enchondromas and hemangiomas developed in almost entire body. Exome analyses of patient’s and her parents’ blood cells identified a mutation in a function-unknown gene (Gene Z). No mutations of Gene Z have been found in other cartilage-forming tumors so far. To investigate the significance of mutant Z protein, we have established iPS cells from the patient and induced chondrogenic differentiation. The results clearly indicated that cells with mutant Z have abnormal chondrogenic property, suggesting the involvement of mutant Z in cartilage-forming tumor. For further investigation, we are now trying to identify the binding protein.

Research Products

• [Journal Article] Enhanced chondrogenesis of induced pluripotent stem cells from patients with neonatal-onset multisystem inflammatory disease occurs via the caspase 1-independent cAMP/protein kinase A/CREB pathway (2015)
  • Author(s): Yokoyama, K. Ikeya, M. Umeda, K. Oda, H. Nodomi, S. Nasu, A. Matsumoto, Y. Izawa, K. Horigome, K. Kusaka, T. Tanaka, T. Saito, M. K. Yasumi, T. Nishikomori, R. Ohara, O. Nakayama, N. Nakahata, T. Heike, T. Toguchida, J.
  • Journal Title: Arthritis Rheumatol Volume: 67 Issue: 1 Pages: 302-314
  • DOI: 10.1002/art.38912
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Derivation of mesenchymal stromal cells from pluripotent stem cells through a neural crest lineage using small molecule compounds with defined media. (2014)
  • Author(s): Fukuta M, Nakai Y, Kirino K, Nakagawa M, Sekiguchi K, Nagata S, Matsumoto Y, Yamamoto T, Umeda K, Heike T, Okumura N, Koizumi N, Sato T, Nakahata T, Saito M, Otsuka T, Kinoshita S, Ueno M, Ikeya M, Toguchida J.
  • Journal Title: PLOS ONE Volume: 9 Issue: 12 Pages: e112291-e112291
  • DOI: 10.1371/journal.pone.0112291
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] IGF2 Preserves Osteosarcoma Cell Survival by Creating an Autophagic State of Dormancy That Protects Cells against Chemotherapeutic Stress (2014)
  • Author(s): Shimizu T, Sugihara E, Yamaguchi-Iwai S, Tamaki S, Koyama Y, Kamel W, Ueki A, Ishikawa T, Chiyoda T, Osuka S, Onishi N, Ikeda H, Kamei J, Matsuo K, Fukuchi Y, Nagai T, Toguchida J, Toyama Y, Muto A, Saya H
  • Journal Title: Cancer Res Volume: 74 Issue: 22 Pages: 6531-6541
  • DOI: 10.1158/0008-5472.can-14-0914
  • Peer Reviewed
• [Journal Article] Unique mutation portraits and frequent COL2A1 gene alteration in chondrosarcoma. (2014)
  • Author(s): Totoki Y, Yoshida A, Hosoda F, Nakamura H, Hama N, Ogura K, Yoshida A, Fujiwara T, Arai Y, Toguchida J, Tsuda H, Miyano S, Kawai A, Shibata T.
  • Journal Title: Genome Res Volume: 24 Issue: 9 Pages: 1411-1420
  • DOI: 10.1101/gr.160598.113
  • Peer Reviewed
• [Journal Article] AFAP1L1, a novel associating partner with vinculin, modulates cellular morphology and motility, and promotes the progression of colorectal cancers. (2014)
  • Author(s): Takahashi R, Nagayama S, Furu M, Kajita Y, Jin Y, Kato T, Imoto S, Sakai Y, Toguchida J.
  • Journal Title: Cancer Medicine Volume: なし Issue: 4 Pages: 759-774
  • DOI: 10.1002/cam4.237
  • Peer Reviewed
• [Journal Article] Good Response to Chemotherapy Spares Irradiation for Extrarenal Rhabdoid Tumor Conferring Better Activities of Daily Living (2014)
  • Author(s): Asada N, Kato I, Daifu T, Umeda K, Hiramatsu H, Okamoto T, Toguchida J, Yamawaki S, Yoshikawa K, Adachi S, Heike T, Watanabe K.
  • Journal Title: J Pediatr Hematol Oncol. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Genetically Matched Human iPS Cells Reveal that Propensity for Cartilage and Bone Differentiation Differs with Clones, not Cell Type of Origin (2013)
  • Author(s): Nasu A
  • Journal Title: PLoS One Volume: 8 Issue: 1 Pages: e53771-e53771
  • DOI: 10.1371/journal.pone.0053771
  • Peer Reviewed
• [Journal Article] Identification of target genes of synovial sarcoma-associated fusion oncoprotein using human DluriDotent stem cells. (2013)
  • Author(s): Hayakawa K, et al.
  • Journal Title: Biochem Biophys Res Commun Volume: 432 Pages: 713-719
  • Peer Reviewed
• [Journal Article] EWS/ATF1 expression induces sarcomas from neural crest-derived cells in mice. (2013)
  • Author(s): Yamada K, et al.
  • Journal Title: J Clin Invest Volume: 123 Pages: 600-610
  • Peer Reviewed
• [Journal Article] The transcription factor Sp3 regulates the expression of a metastasis-related marker of sarcoma, actin filament-associated protein 1-like 1 (AFAP1L1). (2013)
  • Author(s): Kajita Y, et al.
  • Journal Title: PLoS One Volume: 8
  • Peer Reviewed
• [Journal Article] Donor-dependent variations in hepatic differentiation from human-induced pluripotent stem cells. (2012)
  • Author(s): Kajiwara M
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 109 Issue: 31 Pages: 12538-12543
  • DOI: 10.1073/pnas.1209979109
  • Peer Reviewed
• [Presentation] Involvement of epigenetic mechanism in the formation of epithelial structure of synovial sarcoma (2014)
  • Author(s): Hineno S、Tamaki S, Yonghui J, Kawai A, Yoshida A, Okamoto T, Matsuda S, Kato T, Toguchida J
  • Organizer: 第19回CTOS
  • Place of Presentation: Berlin（Germany）
  • Year and Date: 2014-10-17
• [Presentation] Celluler Context Is Important Factor For The Ss18-Ssx-Mediated Transcriptional Regulation (2014)
  • Author(s): Tamaki S、Fukuta M, Hayakawa K, Jin Y, Hineno S, Ikeya M, Kato T, Toguchida J
  • Organizer: 第19回CTOS
  • Place of Presentation: Berlin（Germany）
  • Year and Date: 2014-10-17
• [Presentation] EWS/ATF1誘導性肉腫細胞株由来iPS細胞を用いた発がん研究 (2014)
  • Author(s): 河村真吾、大野貴敏、秋山治彦、山田一成、戸口田淳也、山田泰広
  • Organizer: 第29回日本整形外科学会基礎学術集会
  • Place of Presentation: 城山観光ホテル（鹿児島県鹿児島市）
  • Year and Date: 2014-10-10
• [Presentation] 骨・軟部腫瘍の遺伝子解析 - 最近の進歩 - (2014)
  • Author(s): 戸口田淳也、金永輝、松永一仁、岡本健、松田秀一
  • Organizer: 第29回日本整形外科学会基礎学術集会
  • Place of Presentation: 城山観光ホテル（鹿児島県鹿児島市）
  • Year and Date: 2014-10-09
• [Presentation] EWS/ATF1誘導性肉腫細胞株由来iPS細胞作製の試み (2014)
  • Author(s): 河村真吾、大野貴敏、秋山治彦、山田泰広、戸口田淳也、山田一成
  • Organizer: 第47回日本整形外科学会骨・軟部腫瘍学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-07-18
• [Presentation] 滑膜肉腫の上皮様構造形成におけるエピゲノム制御の関与 (2014)
  • Author(s): 日根野翔、玉置さくら、金永輝、川井章、吉田朗彦、岡本健、松田秀一、加藤友久、戸口田淳也
  • Organizer: 第47回日本整形外科学会骨・軟部腫瘍学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-07-17
• [Presentation] 細胞背景は滑膜肉腫特異的融合タンパクSS18-SSXのエピジェネティック制御において重要である (2014)
  • Author(s): 玉置さくら、福田誠、早川和男、加藤友久、戸口田淳也
  • Organizer: 第47回日本整形外科学会骨・軟部腫瘍学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-07-17
• [Presentation] Mutant IDH promotes chondrogenic, but impirs osteogenic differentiation of human mesenchymal stem cells through epigenetic modulation (2014)
  • Author(s): Yonghui Jin, Hassan Elalaf, Makato Watanabe, Kazuhito Matsunaga, Tomohisa Kato, Takeshi Okamoto, Shuichi Matusda, Junya Toguchida
  • Organizer: 第47回日本整形外科学会骨・軟部腫瘍学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-07-17
• [Presentation] 新規治療戦略の開発をめざした肉腫起源細胞の探索 (2014)
  • Author(s): 戸口田淳也、玉置さくら、福田誠、池谷真、加藤友久、岡本健、松田秀一
  • Organizer: 第87回日本整形外科学会学術総会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2014-05-23
• [Presentation] AFAP1L1 accelerates growth of sarcoma cells in vivo through the association with protein complex in invadopodia. (2012)
  • Author(s): Takahashi R, et al.
  • Organizer: 第17回CTOS
  • Place of Presentation: プラハ(チェコスロバキア)
  • Year and Date: 2012-11-15
• [Presentation] 薬剤誘導型発現ベクターを用いたSYT-SSX融合遺伝子導入iPS細胞の樹立 (2012)
  • Author(s): 早川和男、他.
  • Organizer: 第45回日本整形外科学会骨軟部腫瘍学術集会
  • Place of Presentation: 京王プラザ(東京都)
  • Year and Date: 2012-07-15
• [Presentation] Genetically matched human iPS cells revealed that the propensity for iPS cells to differentiate into cartilage lineage cells differs with clones, but not cell type of origin. (2012)
  • Author(s): Nasu A, et al.
  • Organizer: 第10回ISSCR
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2012-06-15
• [Presentation] Proteomic analysis-based identification of proteins related to differentiation of human iPS cells into cartilage cells. (2012)
  • Author(s): Watanabe M, et al.
  • Organizer: 第10回ISSCR
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2012-06-15
• [Presentation] Establishment and functional analysis of iPS cells with drug-inducible SYT-SSX fusion gene. (2012)
  • Author(s): Fukuta M, et al.
  • Organizer: 第10回ISSCR
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2012-06-14
• [Presentation] 同一ドナーの異なる組織より樹立したiPS細胞の比較検討 (2012)
  • Author(s): 那須輝、他.
  • Organizer: 第11回日本再生医療学会総会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2012-06-13
• [Presentation] 薬剤誘導型発現ベクターを用いたSYT-SSX融合遺伝子導入iPS細胞の樹立 (2012)
  • Author(s): 福田誠、他.
  • Organizer: 第11回日本再生医療学会総会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2012-06-12
• [Presentation] 多能性幹細胞を用いた融合遺伝子標的遺伝子の同定
  • Author(s): 早川和男、池谷真、福田誠、Knut Woltjen、玉置さくら、高原直子、松本佳久、佐藤信吾、大塚隆信、戸口田淳也
  • Organizer: 第46回日本整形外科学会骨・軟部腫瘍学術集会
  • Place of Presentation: 東京ドームホテル（東京都）
• [Presentation] 日本人の軟骨腫瘍におけるIDG遺伝子の突然変異スペクトラ
  • Author(s): 金永輝、Hassan Elalaf、加藤友久、池谷真、永田早苗、仲俣岳晴、岡本健、松田秀一、戸口田淳也
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] 細胞骨格関連タンパクC7059は細胞遊走能を制御して大腸癌進展に関与する
  • Author(s): 長山聡、高橋亮、井元清哉、布留守敏、梶田洋一郎、片桐豊雅、中村祐輔、坂井義治、戸口田淳也
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] 細胞背景は滑膜肉腫特異的融合タンパクSYT-SSXはエピジェネティック制御において重要な因子である
  • Author(s): 玉置さくら、加藤友久、早川和男、福田誠、高原直子、岡本健、戸口田淳也
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] 肉腫発生機構に関する多能性幹細胞からのアプローチ
  • Author(s): 戸口田淳也、福田誠、玉置さくら、早川和男、大塚隆信、岡本健、池谷真、加藤友久
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）