Development of clinical micropeptidome in cancer tissues

• Project/Area Number: 20K07333
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: Abe Yuichi 愛知県がんセンター(研究所), 分子診断TR分野, 主任研究員 (30731632)
• Co-Investigator(Kenkyū-buntansha): 田口 歩 愛知県がんセンター(研究所), 分子診断TR分野, 分野長 (50817567) ; 山口 類 愛知県がんセンター(研究所), システム解析学分野, 分野長 (90380675) ; 松井 佑介 名古屋大学, 医学系研究科(保健), 准教授 (90761495)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: マイクロペプチド / HLAリガンドーム / がん免疫 / プロテオゲノミクス / がん特異的抗原 / 癌特異的抗原 / 癌ワクチン / バイオマーカー / 癌 / 患者由来Xenograft

Outline of Research at the Start

これまでがん変異タンパク質が多数報告されたが、既存の解析プロトコルではその原理上測定できない分子群が存在し、一例として、Small open reading frameから翻訳される「がんマイクロペプチド」が挙げられる。がん培養細胞にて機能制御を行うマイクロペプチドが実証されたが、臨床検体のマイクロペプチド網羅的測定系は未だ不足している。
従って本研究の目的は、臨床検体からの高感度マイクロペプチド分離法、ならびに同定用
カスタムイプライン構築である。培養細胞を用いた解析プロトコルの最適化から、膵がんPatient-derived xenograftによる患者特異的マイクロペプチド同定を試みる。

Outline of Final Research Achievements

From pan-cancer proteogenomics analysis, tumor-specific antigens such as mutated proteins or non-coding RNA-derived micropeptides have been identified and are gaining attention as promising targets for cancer immunotherapy. In this study, our objective is to establish a micropeptide pre-processing method and identify cancer-specific antigens derived from micropeptides.
Using our unique measurement system, we have successfully identified over 10,000 cancer antigens from culture cell lines and patient-derived xenograft (PDX) tissues. Furthermore, even through de novo peptide sequencing, we have identified more than 3,000 antigens with high presentation scores. Currently, we are focused on developing a patient-specific proteogenomics search and preparing for the screening of highly immunogenic antigens.

Academic Significance and Societal Importance of the Research Achievements

肺がん、膵がん、転移性大腸がんなどに代表される難治がんは、早期診断が困難であり、診断された時には現行の治療法では治癒しがたい。解析手法の進歩によって、難治がんの分子生物学的知見が集積しつつあるものの、有効な診断・治療法の開発には至っていない。がんワクチン療法は、免疫チェックポイント阻害剤との併用など、複合的がん免疫療法の１つとして大きな期待が寄せられており、本研究提案は、これら難治がんの予後の革新的な改善に貢献できる。愛知県がんセンターで整備されている難治がんPDXライブラリへと解析対象を拡張していくことで、これら難治がんの予後改善への貢献といった発展的成果も期待できる。

Research Products

• [Journal Article] Integration of pharmacoproteomic and computational approaches reveals the cellular signal transduction pathways affected by apatinib in gastric cancer cell lines (2023)
  • Author(s): Nojima Y, Aoki M, Re S, Hirano H, Abe Y, Narumi R, Muraoka S, Shoji H, Honda K, Tomonaga T, Mizuguchi K, Boku N, Adachi J.
  • Journal Title: Comput Struct Biotechnol J. Volume: Mar 15;21 Pages: 2172-2187
  • DOI: 10.1016/j.csbj.2023.03.006
  • Peer Reviewed / Open Access
• [Journal Article] Src activation in lipid rafts confers epithelial cells with invasive potential to escape from apical extrusion during cell competition (2022)
  • Author(s): Kajiwara Kentaro、Chen Ping-Kuan、Abe Yuichi、Okuda Satoru、Kon Shunsuke、Adachi Jun、Tomonaga Takeshi、Fujita Yasuyuki、Okada Masato
  • Journal Title: Current Biology Volume: 32 Issue: 16 Pages: 3460-3476
  • DOI: 10.1016/j.cub.2022.06.038
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Systematic identification of ALK substrates by integrated phosphoproteome and interactome analysis. (2022)
  • Author(s): Adachi, J., Kakudo, A., Takada, Y., Isoyama, J., Ikemoto, N., Abe, Y., Narumi, R., Muraoka, S., Gunji, D., Hara, Y., Katayama, R., and Tomonaga, T.
  • Journal Title: Life Sci Alliance Volume: 5 Issue: 8 Pages: e202101202-e202101202
  • DOI: 10.26508/lsa.202101202
  • Peer Reviewed / Open Access
• [Journal Article] Temporal dynamics from phosphoproteomics using endoscopic biopsy specimens provides new therapeutic targets in stage IV gastric cancer (2022)
  • Author(s): Hirano H, Abe Y, Nojima Y, Aoki M, Shoji H, Isoyama J, Honda K, Boku N, Mizuguchi K, Tomonaga T, Adachi J.
  • Journal Title: Sci Rep. Volume: 12(1) Issue: 1 Pages: 4419-4419
  • DOI: 10.1038/s41598-022-08430-7
  • Peer Reviewed / Open Access
• [Journal Article] GSK3 inhibition circumvents and overcomes acquired lorlatinib resistance in ALK-rearranged non-small-cell lung cancer (2022)
  • Author(s): Shimizu Yuki、Okada Koutaroh、Adachi Jun、Abe Yuichi、Narumi Ryohei、Uchibori Ken、Yanagitani Noriko、Koike Sumie、Takagi Satoshi、Nishio Makoto、Fujita Naoya、Katayama Ryohei
  • Journal Title: npj Precision Oncology Volume: 6 Issue: 1 Pages: 16-16
  • DOI: 10.1038/s41698-022-00260-0
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal microbe-dependent ω3 lipid metabolite αKetoA prevents inflammatory diseases in mice and cynomolgus macaques (2022)
  • Author(s): Nagatake T, Kishino S, Urano E, et al.
  • Journal Title: Mucosal Immunology Volume: 15 Issue: 2 Pages: 289-300
  • DOI: 10.1038/s41385-021-00477-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ossible Therapeutic Strategy Involving the Purine Synthesis Pathway Regulated by ITK in Tongue Squamous Cell Carcinoma. (2021)
  • Author(s): Onidani K, Miura N, Sugiura Y, Abe Y, Watabe Y, Kakuya T, Mori T, Yoshimoto S, Adachi J, Kiyoi T, Kabe Y, Suematsu M, Tomonaga T, Shibahara T, Honda K.
  • Journal Title: Cancers Volume: 13 Issue: 13 Pages: 3333-3333
  • DOI: 10.3390/cancers13133333
  • Peer Reviewed / Open Access
• [Journal Article] RoDiCE: robust differential protein co-expression analysis for cancer complexome (2021)
  • Author(s): Matsui Yusuke、Abe Yuichi、Uno Kohei、Miyano Satoru
  • Journal Title: Bioinformatics Volume: 38 Issue: 5 Pages: 1269-1276
  • DOI: 10.1093/bioinformatics/btab612
  • Peer Reviewed
• [Journal Article] Identification of Blood-Based Biomarkers for the Prediction of the Response to Neoadjuvant Chemoradiation in Rectal Cancer (2021)
  • Author(s): Dayde Delphine, Gunther Jillian, Hirayama Yutaka, Weksberg David C., Boutin Adam, Parhy Gargy, Aguilar-Bonavides Clemente, Wang Hong, Katayama Hiroyuki, Abe Yuichi…, Taguchi Ayumu
  • Journal Title: Cancers Volume: 13 Issue: 14 Pages: 3642-3642
  • DOI: 10.3390/cancers13143642
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pharmacological Inhibition of miR-130 Family Suppresses Bladder Tumor Growth by Targeting Various Oncogenic Pathways via PTPN1 (2021)
  • Author(s): Monoe Yuya, Jingushi Kentaro, Kawase Akitaka, Hirono Takayuki, Hirose Ryo, Nakatsuji Yoshino, Kitae Kaori, Ueda Yuko, Hase Hiroaki, Abe Yuichi, Adachi Jun, Tomonaga Takeshi, Tsujikawa Kazutake
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 9 Pages: 4751-4751
  • DOI: 10.3390/ijms22094751
  • Peer Reviewed / Open Access
• [Journal Article] 12-Hydroxyeicosapentaenoic acid inhibits foam cell formation and ameliorates high-fat diet-induced pathology of atherosclerosis in mice (2021)
  • Author(s): Nagatake T, Shibata Y, Morimoto S, Node E, Sawane K, Hirata SI, Adachi J, Abe Y, Isoyama J, Saika A, Hosomi K, Tomonaga T, and Kunisawa J.
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 10426-10426
  • DOI: 10.1038/s41598-021-89707-1
  • Peer Reviewed / Open Access
• [Presentation] 免疫グロブリン結合タンパク質の高深度プロテオーム解析と、新規がんバイオマーカー探索研究への応用 (2022)
  • Author(s): 阿部雄一・磯村久徳・田口歩
  • Organizer: 日本プロテオーム学会2022
• [Presentation] 患者由来試料を用いたリン酸化プロテオーム解析手法の開発と胃がん生検試料への 応用 (2021)
  • Author(s): 阿部雄一, 平野秀和, 青木雅彦, 庄司広和, 鬼谷薫, 本田一文, 朴成和, 朝長毅, 足立淳
  • Organizer: 日本プロテオーム学会2021年大会2020年度奨励賞受賞講演
  • Invited
• [Presentation] emporal omics profiling using a mouse model of nonalcoholic steatohepatitis-associated hepatocellular carcinoma (2021)
  • Author(s): Abe Y, Shuang Z, Mizuno K, Tanaka I、Ito T, Ishigami M, Fujishiro M, Suganami T, Taguchi A
  • Organizer: 第80回日本がん学会学術総会
• [Patent(Industrial Property Rights)] 抗原分子の単離方法 (2022)
  • Inventor(s): 田口歩、阿部雄一、奥本泰秀
  • Industrial Property Rights Holder: 田口歩、阿部雄一、奥本泰秀
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2022-152089
  • Filing Date: 2022