Identification of novel drug-responsive cell subpopulations with chromatin accessibility analysis of head and neck cancer

• Project/Area Number: 20K07383
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: MORI TAISUKE 国立研究開発法人国立がん研究センター, 中央病院, 医員 (00296708)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2022: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 頭頸部癌 / ゲノム解析 / 再発・多発 / ヘテロジェネイティ / 治療法開発 / 頭頸部扁平上皮癌 / TP53 / 時間空間的解析 / 治療開発 / 頭頸部がん / クロマチン解析 / ゲノム変異 / トランスクリプトーム / クロマチンアクセシビリティ

Outline of Research at the Start

重要な癌抑制遺伝子であるTP53ステータスの明確なコホートのゲノム・トランスクリプトーム解析を行い、異常の蓄積から空間的不均一性、“初診時”と“再発時”の時間的不均一性を明らかにし、サブポピュレーション亜集団特定を行う。この亜集団の代表例の凍結サンプルからSingle Cell ATAC-Seq (scATAC-Seq) によるゲノムワイドなオープンクロマチン領域を探索する。このクロマチン領域のアクセシビリティの変化から遺伝子発現に関連するゲノム領域の特定と結合転写因子の推定から薬物治療への応答に関与する新規細胞亜集団、すなわち、レスポンダー、ノンレスポンダーの亜集団特定を行う。

Outline of Final Research Achievements

To understand the heterogeneity of head and neck squamous cell carcinoma and the accumulation of genomic aberrations and associated treatment resistance, we analyzed the subpopulations that define diversity together with the mechanisms of tumorigenesis, HPV types, and morphological changes. DNA was extracted from 17 cases, and exome analysis of cancer-related genes was performed. In addition, more than 50 cases of multi-region exome analysis were completed. In addition, we have analyzed recurrent cases including temporal changes and metastatic lymph nodes. This has revealed the presence of at least three clones within a single tumor and potential drug target drivers.

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Academic Significance and Societal Importance of the Research Achievements

頭頸部癌はアルコールやタバコの要因のみならず、Ｈuman Papiloma VirsやＥpstein-Berr Virus感染,
近年では血液腫瘍に対する骨髄移植後の移植片対宿主病変（Ｇｒａｆｔ　Ｖｅｒｓｕｓ　Ｈｏｓｔ　Ｄisease/GVHD)を起因とした多発、再発がんが問題となっている。これらの疾患の本質は、フィールドキャンサライぜーションと呼称される領域全体のゲノム変異の蓄積である。ほん研究の成果はそれらの領域的なヘテロジェネイティを理解すること、腫瘍の薬剤耐性のメカニズムを理解し、治療方針や予防、再発のリスク評価などの患者のフォローアップ方法のエビデンスを確立することにある。

Research Products

• [Journal Article] Frequent CD30 Expression in an Emerging Group of Mesenchymal Tumors With NTRK, BRAF, RAF1, or RET Fusions (2023)
  • Author(s): Kojima Naoki、Mori Taisuke、Motoi Toru、Kobayashi Eisuke、Yoshida Masayuki、Yatabe Yasushi、Ichikawa Hitoshi、Kawai Akira、Yonemori Kan、Antonescu Cristina R.、Yoshida Akihiko
  • Journal Title: Modern Pathology Volume: 36 Issue: 4 Pages: 100083-100083
  • DOI: 10.1016/j.modpat.2022.100083
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RIOK2 Contributes to Cell Growth and Protein Synthesis in Human Oral Squamous Cell Carcinoma (2022)
  • Author(s): Matsuzaki Yusuke、Naito Yutaka、Miura Nami、Mori Taisuke、Watabe Yukio、Yoshimoto Seiichi、Shibahara Takahiko、Takano Masayuki、Honda Kazufumi
  • Journal Title: Current Oncology Volume: 30 Issue: 1 Pages: 381-391
  • DOI: 10.3390/curroncol30010031
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of the p53‐p16/RB pathway control mechanism in early‐stage carcinogenesis in head and neck squamous cell carcinoma (2022)
  • Author(s): Mori Taisuke
  • Journal Title: Pathology International Volume: 72 Issue: 12 Pages: 577-588
  • DOI: 10.1111/pin.13279
  • Peer Reviewed
• [Journal Article] Clinical impact of p16 positivity in nasopharyngeal carcinoma (2022)
  • Author(s): Shimizu Yuri、Murakami Naoya、Mori Taisuke、Takahashi Kana、Kubo Yuko、Yoshimoto Seiichi、Honma Yoshitaka、Nakamura Satoshi、Okamoto Hiroyuki、Iijima Kotaro、Takahashi Ayaka、Kaneda Tomoya、Kashihara Tairo、Inaba Koji、Okuma Kae、Nakayama Yuko、Igaki Hiroshi、Itami Jun
  • Journal Title: Laryngoscope Investigative Otolaryngology Volume: 7 Issue: 4 Pages: 994-1001
  • DOI: 10.1002/lio2.832
  • Peer Reviewed
• [Journal Article] Non-Robustness of Ang’s Risk Classification in Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma in Japanese Patients (2022)
  • Author(s): Itami Jun、Kobayashi Kenya、Mori Taisuke、Honma Yoshitaka、Kubo Yuko、Murakami Naoya、Omura Go、Okuma Kae、Inaba Koji、Takahashi Kana、Kashihara Tairo、Shimizu Yuri、Takahashi Ayaka、Nakayama Yuko、Matsumoto Fumihiko、Yoshimoto Seiichi、Igaki Hiroshi
  • Journal Title: Cancers Volume: 14 Issue: 10 Pages: 2442-2442
  • DOI: 10.3390/cancers14102442
  • Peer Reviewed
• [Journal Article] Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments (2022)
  • Author(s): Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, Kamada T, Irie T, Okumura G, Kono H, Ito D, Fujii R, Watanabe S, Sai A, Aokage K, Suzuki J, Ishii G, Kuwata T, Sakamoto N, Kawazu M, Ueno T, Mori T, Yamazaki N, Tsuboi M, Yatabe Y, Kinoshita T, Doi T, Shitara K, Mano H, Nishikawa H
  • Journal Title: Cancer Cell Volume: 40 Issue: 2 Pages: 201-218
  • DOI: 10.1016/j.ccell.2022.01.001
  • Peer Reviewed / Open Access
• [Journal Article] 頭頸部扁平上皮癌における遺伝子異常 (2022)
  • Author(s): 森 泰昌
  • Journal Title: 耳鼻咽喉科 Volume: １ Pages: 667-675
  • Int'l Joint Research
• [Journal Article] がんゲノム医療時代の分子腫瘍学 (2022)
  • Author(s): 森 泰昌
  • Journal Title: 病理と臨床 Volume: 臨時増刊号 Pages: 178-183
  • Int'l Joint Research
• [Journal Article] 口腔癌update 特集編集者/執筆 前がん病変から早期口腔癌、進行期口腔癌病変における時間的、空間的遺伝子変異 (2022)
  • Author(s): 森 泰昌
  • Journal Title: 病理と臨床 Volume: 40 Pages: 57-63
  • Int'l Joint Research
• [Journal Article] Identification of novel SSX1 fusions in synovial sarcoma. (2021)
  • Author(s): Yoshida Akihiko、Arai Yasuhito、Satomi Kaishi、Kubo Takashi、Ryo Eijitsu、Matsushita Yuko、Hama Natsuko、Sudo Kazuki、Komiyama Motokiyo、Yatabe Yasushi、Shibata Tatsuhiro、Ichikawa Hitoshi、Ichimura Koichi、Kawai Akira、Mori Taisuke.
  • Journal Title: Modern Pathology Volume: 35 Issue: 2 Pages: 228-239
  • DOI: 10.1038/s41379-021-00910-x
  • Peer Reviewed / Open Access
• [Journal Article] MicroSEC; Sequence error filtering pipeline for formalin-fixed and paraffin-embedded samples. (2021)
  • Author(s): Ikegami M, Kohsaka S, Hirose T, Ueno T, Inoue S, Konomata N, Yamauchi H, Mori T, Sekine S, Inamoto Y, Yatabe Y, Kobayashi H, Tanaka S, Mano H.
  • Journal Title: Commun Biol Volume: 4 Issue: 1 Pages: 1396-1396
  • DOI: 10.1038/s42003-021-02930-4
  • Peer Reviewed / Open Access
• [Journal Article] Cutaneous Primary NUT Carcinoma With BRD3-NUTM1 Fusion (2021)
  • Author(s): Nishimura Yuuki、Ryo Eijitsu、Yamazaki Naoya、Yatabe Yasushi、Mori Taisuke
  • Journal Title: American Journal of Surgical Pathology Volume: 45 Issue: 11 Pages: 1582-1584
  • DOI: 10.1097/pas.0000000000001801
  • Peer Reviewed / Open Access
• [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] RB1 gene mutations are a distinct predictive factor in Merkel cell carcinoma (2021)
  • Author(s): Muto Yusuke、Ryo Eijitsu、Namikawa Kenjiro、Takahashi Akira、Ogata Dai、Fujimura Taku、Yatabe Yasushi、Aiba Setsuya、Yamazaki Naoya、Mori Taisuke
  • Journal Title: Pathology International Volume: 71 Issue: 5 Pages: 337-347
  • DOI: 10.1111/pin.13090
  • Peer Reviewed / Open Access
• [Journal Article] Pathological processes and pretreatment cytologic diagnosis of neuroendocrine carcinoma of the endometrium: addendum report of the Kansai Clinical Oncology Group/Intergroup study in Japan (2021)
  • Author(s): Matsumoto Harunobu、Nasu Kaei、Shikama Ayumi、Shiozaki Takaya、Futagami Masayuki、Kai Kentaro、Mori Taisuke、Yano Mitsutake、Yamada Takashi、Teramoto Norihiro
  • Journal Title: Medical Molecular Morphology Volume: - Issue: 3 Pages: 237-244
  • DOI: 10.1007/s00795-021-00288-4
  • Peer Reviewed
• [Journal Article] BP180 Is a Prognostic Factor in Head and Neck Squamous Cell Carcinoma (2021)
  • Author(s): MENG XUE、MATSUMOTO FUMIHIKO、MORI TAISUKE、MIURA NAMI、INO YOSHINORI、ONIDANI KAORU、KOBAYASHI KENYA、MATSUZAKI YUSUKE、YOSHIMOTO SEIICHI、IKEDA KATSUHISA、HONDA KAZUFUMI
  • Journal Title: Anticancer Research Volume: 41 Issue: 2 Pages: 1089-1099
  • DOI: 10.21873/anticanres.14867
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic Value of Epithelial Cell Adhesion Molecules in T1‐2N0M0 Glottic Cancer (2020)
  • Author(s): Murakami Naoya、Mori Taisuke、Machida Ryunosuke、Kodaira Takeshi、Ito Yoshinori、Shikama Naoto、Konishi Koji、Matsumoto Yasuo、Murakami Yuji、Nakamura Naoki、Yamashita Hideomi、Yorozu Atsunori、Yoshimura Michio、Inoue Koichi、Nozaki Miwako、Ishikura Satoshi、Itami Jun、Nishimura Yasumasa、Kagami Yoshikazu
  • Journal Title: The Laryngoscope Volume: - Issue: 7 Pages: 1522-1527
  • DOI: 10.1002/lary.29348
  • Peer Reviewed
• [Journal Article] Full-coverage TP53 deep sequencing of recurrent head and neck squamous cell carcinoma facilitates prognostic assessment after recurrence. (2020)
  • Author(s): Kobayashi K, Yoshimoto S, Ando M, Matsumoto F, Murakami N, Omura G, Honma Y, Matsumoto Y, Ikeda A, Sakai A, Eguchi K, Ito A, Eigitsu R, Yatabe Y, Mori T.
  • Journal Title: Oral oncology Volume: 113 Pages: 105091-105091
  • DOI: 10.1016/j.oraloncology.2020.105091
  • Peer Reviewed / Open Access
• [Presentation] 細胞診とシームレスに行うコンパクトなカスタマイズパネルの実際 (2022)
  • Author(s): 森 泰昌
  • Organizer: 第６３回日本臨床細胞学会
  • Invited
• [Presentation] 口腔癌とゲノム医療、口腔細胞診検体のゲノム医療への応用 (2022)
  • Author(s): 森 泰昌
  • Organizer: 第６１回日本臨床細胞学会総会
  • Invited
• [Presentation] 頭頸部扁平上皮癌における p53-p16/RB 経路制御機構と早期癌発症および悪性度への関与 (2020)
  • Author(s): 森 泰昌
  • Organizer: 第66回日本病理学会秋期特別総会
  • Invited