Exploration of the origin of intratumoral heterogeneity in squamous cell carcinoma by single-cell analysis

• Project/Area Number: 20K08698
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Nippon Medical School
• Principal Investigator: Saeki Hidehisa 日本医科大学, 大学院医学研究科, 大学院教授 (80235093)
• Co-Investigator(Kenkyū-buntansha): 長田 真一 日本医科大学, 医学部, 准教授 (00244484) ; 平谷 伊智朗 国立研究開発法人理化学研究所, 生命機能科学研究センター, チームリーダー (40583753)
• 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: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 有棘細胞がん / 腫瘍内不均一性 / 微小環境 / RNA-Seq / シグナル伝達 / 3次元構造 / シングルセル解析 / 上皮間葉転換 / 有棘細胞癌 / がん微小環境

Outline of Research at the Start

有棘細胞がんの培養細胞（2次元）を、マウスの皮下に注射（すなわち微小環境を提供）すると、3次元のがん組織ができる。がん細胞が2次元から3次元に転換する時に、どのような遺伝子の発現の変化が起こるのかを、最高レベルの遺伝子検出能力をもつ手法を用いて、単一細胞レベルで解析する。そして、検出した遺伝子が、有棘細胞がんの腫瘍内不均一性の獲得、治療抵抗性、再発・転移にどのような役割をしているのかを調べる。

Outline of Final Research Achievements

To investigate the mechanism of intratumor heterogeneity in cutaneous squamous cell carcinoma (cSCC), we established an experimental system in which cultured cSCC cells (2D) were subcutaneously injected into mice of the same strain to form cSCC tissues (3D), thus reproducing the cancer microenvironment. We then compared the genes expressed in cultured cSCC cells and cSCC tissues by comprehensive RNA-Seq analysis. Pathway analysis of 1488 genes whose expression levels were significantly up- or down-regulated in cSCC tissues revealed that pathways involved in promoting inflammation, cellular immune response, and cell adhesion were highly activated.

Academic Significance and Societal Importance of the Research Achievements

2次元の培養細胞を用いたがん研究は、シグナル伝達経路の解明をはじめ、がん研究を大きく発展させてきたが、3次元組織でのがん細胞の振る舞いを必ずしも反映しているとは言えなかった。本研究は、この2次元と3次元のギャップを埋め、がん微小環境が生じるメカニズムの解明を目指した研究で、3次元のがん組織で活性化している複数のシグナル経路を見出した。本研究の成果は、がんの腫瘍内不均一性の解明と、高齢者に増加している有棘細胞がんの新たな治療法の開発につながることが期待される。

Research Products

• [Journal Article] Barrier Factors of Adherence to Dupilumab Self-Injection for Severe Allergic Disease: A Non-Interventional Open-Label Study (2023)
  • Author(s): Hosoya K, Komachi T, Masaki K, Suzaki I, Saeki H, Kanda N, Nozaki M, Kamide Y, Matsuwaki Y, Kobayashi Y, Ogino E, Osada SI et al.
  • Journal Title: Patient Preference and Adherence Volume: Volume 17 Pages: 861-872
  • DOI: 10.2147/ppa.s389865
  • Peer Reviewed / Open Access
• [Journal Article] Recurrence or de novo? Intradermal Basal Cell Carcinoma of the Scrotum: A Report of Two Cases (2023)
  • Author(s): Yamazaki Kaori、Maejima Maho、Saeki Hidehisa、Osada Shin-Ichi
  • Journal Title: Dermatopathology Volume: 10 Issue: 2 Pages: 128-135
  • DOI: 10.3390/dermatopathology10020019
  • Peer Reviewed / Open Access
• [Journal Article] Difamilast ointment in adult patients with atopic dermatitis: A phase 3 randomized, double-blind, vehicle-controlled trial (2022)
  • Author(s): Saeki Hidehisa、Ito Kensuke、Yokota Daisuke、Tsubouchi Hidetsugu
  • Journal Title: Journal of the American Academy of Dermatology Volume: 86 Issue: 3 Pages: 607-614
  • DOI: 10.1016/j.jaad.2021.10.027
  • Peer Reviewed / Open Access
• [Journal Article] Real‐world blood examination screening data before initiation of biologics for psoriasis patients (2022)
  • Author(s): Ozaki Saeko、Ichiyama Susumu、Ito Michiko、Hoashi Toshihiko、Kanda Naoko、Saeki Hidehisa
  • Journal Title: The Journal of Dermatology Volume: 49 Issue: 5 Pages: 534-538
  • DOI: 10.1111/1346-8138.16333
  • Peer Reviewed
• [Journal Article] Effectiveness of brodalumab in achieving treatment satisfaction for patients with plaque psoriasis: The ProLOGUE study (2022)
  • Author(s): Imafuku Shinichi、Ohata Chika、Okubo Yukari、Tobita Rie、Saeki Hidehisa、Mabuchi Tomotaka、Hashimoto Yuki、Murotani Kenta、Kitabayashi Hiroki、Kanai Yasumasa
  • Journal Title: Journal of Dermatological Science Volume: 105 Issue: 3 Pages: 176-184
  • DOI: 10.1016/j.jdermsci.2022.02.007
  • Peer Reviewed / Open Access
• [Journal Article] Difamilast Ointment in Japanese Adult and Pediatric Patients with Atopic Dermatitis: A Phase III, Long-Term, Open-Label Study (2022)
  • Author(s): Saeki Hidehisa、Imamura Tomomi、Yokota Daisuke、Tsubouchi Hidetsugu
  • Journal Title: Dermatology and Therapy Volume: 12 Issue: 7 Pages: 1589-1601
  • DOI: 10.1007/s13555-022-00751-9
  • Peer Reviewed / Open Access
• [Journal Article] A phase 3 randomized, multicenter, double-blind study to evaluate the safety of upadacitinib in combination with topical corticosteroids in adolescent and adult patients with moderate-to-severe atopic dermatitis in Japan (Rising Up): An interim 24-week analysis (2022)
  • Author(s): Katoh Norito、Ohya Yukihiro、Murota Hiroyuki、Ikeda Masanori、Hu Xiaofei、Ikeda Kimitoshi、Liu John、Sasaki Takuya、Chu Alvina D.、Teixeira Henrique D.、Saeki Hidehisa
  • Journal Title: JAAD International Volume: 6 Pages: 27-36
  • DOI: 10.1016/j.jdin.2021.11.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An economic evaluation of risankizumab versus other biologic treatments of moderate to severe plaque psoriasis in Japan (2022)
  • Author(s): Saeki Hidehisa、Ishii Kanako、Joshi Avani、Bensimon Arielle G.、Yang Hongbo、Kawaguchi Isao
  • Journal Title: Journal of Dermatological Treatment Volume: 33 Issue: 1 Pages: 229-239
  • DOI: 10.1080/09546634.2020.1744505
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of standard treatments for managing adult Japanese patients with inadequately controlled moderate‐to‐severe atopic dermatitis: Two‐year data from the <scp>ADDRESS‐J</scp> disease registry (2022)
  • Author(s): Katoh Norito、Saeki Hidehisa、Kataoka Yoko、Etoh Takafumi、Teramukai Satoshi、Takagi Hiroki、Fujita Hiroyuki、Ardeleanu Marius、Rizova Elena、Arima Kazuhiko、the ADDRESS‐J Investigators
  • Journal Title: The Journal of Dermatology Volume: 49 Issue: 9 Pages: 903-911
  • DOI: 10.1111/1346-8138.16485
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular Mechanisms and Targeted Therapies of Advanced Basal Cell Carcinoma (2022)
  • Author(s): Hoashi Toshihiko、Kanda Naoko、Saeki Hidehisa
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 19 Pages: 11968-11968
  • DOI: 10.3390/ijms231911968
  • Peer Reviewed / Open Access
• [Journal Article] Work productivity in real‐life employed patients with plaque psoriasis: Results from the ProLOGUE study (2022)
  • Author(s): Saeki Hidehisa、Kanai Yasumasa、Murotani Kenta、Ito Kei、Miyagi Takuya、Takahashi Hidetoshi、Tada Yayoi、Higashiyama Mari、Hashimoto Yuki、Kitabayashi Hiroki、Imafuku Shinichi
  • Journal Title: The Journal of Dermatology Volume: 49 Issue: 10 Pages: 970-978
  • DOI: 10.1111/1346-8138.16517
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Proactive versus Rank-Down Topical Corticosteroid Therapy for Maintenance of Remission in Pediatric Atopic Dermatitis: A Randomized, Open-Label, Active-Controlled, Parallel-Group Study (Anticipate Study) (2022)
  • Author(s): Kamiya Koji、Saeki Hidehisa、Tokura Yoshiki、Yoshihara Shigemi、Sugai Junichi、Ohtsuki Mamitaro
  • Journal Title: Journal of Clinical Medicine Volume: 11 Issue: 21 Pages: 6477-6477
  • DOI: 10.3390/jcm11216477
  • Peer Reviewed / Open Access
• [Journal Article] Long-term 2-year safety and efficacy of tralokinumab in adults with moderate-to-severe atopic dermatitis: Interim analysis of the ECZTEND open-label extension trial (2022)
  • Author(s): Blauvelt Andrew、Langley Richard G.、Lacour Jean-Philippe、Toth Darryl、Laquer Vivian、Beissert Stefan、Wollenberg Andreas、Herranz Pedro、Pink Andrew E.、Peris Ketty、Fangel Stine、Gjerum Le、Corriveau Joshua、Saeki Hidehisa、Warren Richard B.、Simpson Eric、Reich Kristian
  • Journal Title: Journal of the American Academy of Dermatology Volume: 87 Issue: 4 Pages: 815-824
  • DOI: 10.1016/j.jaad.2022.07.019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pooled Safety Analysis of Baricitinib in Adult Participants with Atopic Dermatitis in the Japanese Subpopulation from Six Randomized Clinical Trials (2022)
  • Author(s): Katoh Norito、Takita Yasushi、Isaka Yoshitaka、Nishikawa Atsushi、Torisu-Itakura Hitoe、Saeki Hidehisa
  • Journal Title: Dermatology and Therapy Volume: 12 Issue: 12 Pages: 2765-2779
  • DOI: 10.1007/s13555-022-00828-5
  • Peer Reviewed / Open Access
• [Journal Article] Collagen XVII deficiency alters epidermal patterning. (2022)
  • Author(s): Wang Y, Kitahata H, Kosumi H, Watanabe M, Fujimura Y, Takashima S, Osada SI, Hirose T, Nishie W, Nagayama M, Shimizu H, Natsuga K.
  • Journal Title: Lab Invest. Volume: - Issue: 6 Pages: 581-588
  • DOI: 10.1038/s41374-022-00738-2
  • Peer Reviewed
• [Journal Article] Large-Scale Chromatin Rearrangements in Cancer (2022)
  • Author(s): Yamaguchi Kosuke、Chen Xiaoying、Oji Asami、Hiratani Ichiro、Defossez Pierre-Antoine
  • Journal Title: Cancers Volume: 14 Issue: 10 Pages: 2384-2384
  • DOI: 10.3390/cancers14102384
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study (2020)
  • Author(s): Nakagawa Hidemi、Nemoto Osamu、Igarashi Atsuyuki、Saeki Hidehisa、Kaino Hironobu、Nagata Takeshi
  • Journal Title: Journal of the American Academy of Dermatology Volume: 82 Issue: 4 Pages: 823-831
  • DOI: 10.1016/j.jaad.2019.12.015
  • Peer Reviewed
• [Journal Article] Japanese guidelines for atopic dermatitis 2020 (2020)
  • Author(s): Katoh N, Ohya Y, Ikeda M, Ebihara T, Katayama I, Saeki H, Shimojo N, Tanaka A, Nakahara T, Nagao M, Hide M, Fujita Y, Fujisawa T, Futamura M, Masuda K, Murota H, Yamamoto-Hanada K
  • Journal Title: Allergology International Volume: 69 Issue: 3 Pages: 356-369
  • DOI: 10.1016/j.alit.2020.02.006
  • NAID: 130007877730
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Nutrition and psoriasis (2020)
  • Author(s): Kanda N, Hoashi T, Saeki H
  • Journal Title: Int J Mol Sci Volume: 21 Issue: 15 Pages: 5405-5405
  • DOI: 10.3390/ijms21155405
  • Peer Reviewed
• [Journal Article] ssociations of TNFAIP3 variants with susceptibility to psoriasis vulgaris and psoriasis arthritis in a Japanese population. (2020)
  • Author(s): Momose M, Hirota T, Kikuchi S, Inoue N, Umezawa Y, Nakagawa H, Saeki H, Tamari M, Asahina A
  • Journal Title: J Dermatol Sci Volume: 100 Issue: 3 Pages: 220-222
  • DOI: 10.1016/j.jdermsci.2020.09.005
  • Peer Reviewed
• [Journal Article] Type XVII collagen interacts with the aPKC‐PAR complex and maintains epidermal cell polarity (2020)
  • Author(s): Watanabe Mika、Kosumi Hideyuki、Osada Shin‐Ichi、Takashima Shota、Wang Yunan、Nishie Wataru、Oikawa Tsukasa、Hirose Tomonori、Shimizu Hiroshi、Natsuga Ken
  • Journal Title: Experimental Dermatology Volume: 30 Issue: 1 Pages: 62-67
  • DOI: 10.1111/exd.14196
  • NAID: 120007182933
  • Peer Reviewed
• [Journal Article] Multifaceted Hi-C benchmarking: what makes a difference in chromosome-scale genome scaffolding? (2020)
  • Author(s): Kadota M, Nishimura O, Miura H, Tanaka K, Hiratani I, *Kuraku S.
  • Journal Title: Gigascience Volume: 9 Issue: 1
  • DOI: 10.1093/gigascience/giz158
  • Peer Reviewed / Open Access
• [Journal Article] Microrheology for Hi-C Data Reveals the Spectrum of the Dynamic 3D Genome Organization (2020)
  • Author(s): Soya Shinkai, Takeshi Sugawara, Hisashi Miura, Ichiro Hiratani, Shuichi Onami
  • Journal Title: Biophysical Journal Volume: 118 Issue: 9 Pages: 2220-2228
  • DOI: 10.1016/j.bpj.2020.02.020
  • Peer Reviewed / Open Access
• [Journal Article] Mapping replication timing domains genome wide in single mammalian cells with single-cell DNA replication sequencing (2020)
  • Author(s): Miura Hisashi、Takahashi Saori、Shibata Takahiro、Nagao Koji、Obuse Chikashi、Okumura Katsuzumi、Ogata Masato、Hiratani Ichiro、Takebayashi Shin-ichiro
  • Journal Title: Nature Protocols Volume: 15 Issue: 12 Pages: 4058-4100
  • DOI: 10.1038/s41596-020-0378-5
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of dupilumab in Japanese adults with moderate‐to‐severe atopic dermatitis: a subanalysis of three clinical trials (2019)
  • Author(s): Katoh N.、Kataoka Y.、Saeki H.、Hide M.、Kabashima K.、Etoh T.、Igarashi A.、Imafuku S.、Kawashima M.、Ohtsuki M.、Fujita H.、Arima K.、Takagi H.、Chen Z.、Shumel B.、Ardeleanu M.
  • Journal Title: British Journal of Dermatology Volume: 183 Issue: 1 Pages: 39-51
  • DOI: 10.1111/bjd.18565
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Real-world safety and one-year effectiveness of dupilumab in Japanese patients with atopic dermatitis (2022)
  • Author(s): Fujita H, Suzuki K, Arima K, Saeki H
  • Organizer: Annual Meeting of the American Academy of Dermatology
  • Int'l Joint Research