Exploration of differentiation programs in lung cancers using epigenomic profiling

• Project/Area Number: 20K17192
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Keio University
• Principal Investigator: Sato Takashi 慶應義塾大学, 医学部, 共同研究員 (20464836)
• 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: エピゲノム / 肺癌 / super-enhancer / 肺大細胞神経内分泌癌 / 細胞系統因子 / 転写プログラム / 肺がん / 分化プログラム / 不均一性 / 肺大細胞神経内分泌がん / 可塑性

Outline of Research at the Start

近年の抗癌治療の進歩にも関わらず、肺癌は依然本邦の癌死因第一位の予後不良な疾患である。肺癌患者に対する新たな治療戦略開発の礎となる、病態の理解に向けた革新的な研究戦略が求められている。これまでの研究により、癌の発生する臓器に特徴的なDNA結合因子が癌細胞の状態を制御し、その癌の振る舞いを規定することが示唆されている。研究代表者らは、最新のエピゲノム解析により肺扁平上皮癌において新規サブタイプを同定した。本研究では、これまで解析が困難であったホルマリン固定検体やオルガノイド検体を用いた解析を計画する。各種肺癌における個々の違いや治療耐性のメカニズムを検討し、個別化治療をを向上させることを目指す。

Outline of Final Research Achievements

High-grade neuroendocrine tumors of the lung are especially aggressive with a dismal prognosis. In this study, we aimed to elucidate the heterogeneity of neuroendocrine differentiation in lung cancer with neuroendocrine components by using epigenomic profiling. In the result, our epigenomic profiling identified distinct differentiation subtypes of lung cancer with neuroendocrine components, which may be different from the previously reported classifications based on the expression of lineage transcription factors. Classical neuroendocrine subtype determined by high expression of ASCL1 and NKX2-1 is particularly distinct with more neuroendocrine features compared with the other subtypes.

Academic Significance and Societal Importance of the Research Achievements

大規模な肺癌ゲノム研究によりシグナル伝達分子に数々の体性遺伝子異常が発見されてきたものの、主に肺腺癌に見つかる遺伝子変化を除けば標的治療の開発に結びついていない。一方、肺癌ゲノム研究を通じて癌細胞が細胞系統転写因子の規定する分化プログラムに依存していることも示されてきた。しかし、大多数の肺癌における分化プログラムを規定する分子機構は未だ見つかっておらず、特に肺癌の中でも予後不良である高悪性度神経内分泌腫瘍の分類と特徴付けは確立していなかった。本研究では肺癌における神経内分泌分化の多様性が既知の報告と異なるパターンであることが示唆され、今後肺癌細胞の可塑性と脆弱性の解明につながる可能性がある。

Research Products

• [Journal Article] Exploring Molecular Subtypes of Small-Cell Lung Cancer and Other Pulmonary Neuroendocrine Carcinomas (2022)
  • Author(s): Sato Takashi、Naoki Katsuhiko
  • Journal Title: Haigan Volume: 62 Issue: 4 Pages: 286-291
  • DOI: 10.2482/haigan.62.286
  • ISSN: 0386-9628, 1348-9992
  • Year and Date: 2022-08-20
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptional Circuitry of NKX2-1 and SOX1 Defines an Unrecognized Lineage Subtype of Small-Cell Lung Cancer (2022)
  • Author(s): Kong Ranran、Patel Ayushi S.、Sato Takashi、Jiang Feng、Yoo Seungyeul、Bao Li、Sinha Abhilasha、Tian Yang、Fridrikh Maya、Liu Shuhui、Feng Jie、He Xijing、Jiang Jiantao、Ma Yuefeng、Grullon Karina、Yang Dawei、Powell Charles A.、Beasley Mary Beth、Zhu Jun、Snyder Eric L.、Li Shaomin、Watanabe Hideo
  • Journal Title: American Journal of Respiratory and Critical Care Medicine Volume: 206 Issue: 12 Pages: 1480-1494
  • DOI: 10.1164/rccm.202110-2358oc
  • Peer Reviewed
• [Journal Article] Integrative network analysis of early-stage lung adenocarcinoma identifies aurora kinase inhibition as interceptor of invasion and progression (2022)
  • Author(s): Yoo Seungyeul、Sinha Abhilasha、Yang Dawei、Altorki Nasser K.、Tandon Radhika、Wang Wenhui、Chavez Deebly、Lee Eunjee、Patel Ayushi S.、Sato Takashi、Kong Ranran、Ding Bisen、Schadt Eric E.、Watanabe Hideo、Massion Pierre P.、Borczuk Alain C.、Zhu Jun、Powell Charles A.
  • Journal Title: Nature Communications Volume: 13 Issue: 1
  • DOI: 10.1038/s41467-022-29230-7
  • Peer Reviewed / Open Access
• [Journal Article] Early-Stage Lung Adenocarcinoma MDM2 Genomic Amplification Predicts Clinical Outcome and Response to Targeted Therapy (2022)
  • Author(s): Sinha Abhilasha、Zou Yong、Patel Ayushi S.、Yoo Seungyeul、Jiang Feng、Sato Takashi、Kong Ranran、Watanabe Hideo、Zhu Jun、Massion Pierre P.、Borczuk Alain C.、Powell Charles A.
  • Journal Title: Cancers Volume: 14 Issue: 3 Pages: 708-708
  • DOI: 10.3390/cancers14030708
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptional circuitry of NKX2-1 and SOX1 defines an unrecognized lineage subtype of small cell lung cancer (2022)
  • Author(s): Ranran Kong、Ayushi S. Patel、Takashi Sato、Seungyeul Yoo、Li Bao、Abhilasha Sinha、Feng Jiang、Yang Tian、Maya Fridrikh、Shuhui Liu、Jie Feng、Xijing He、Jiantao Jiang、Yuefeng Ma 、Karina Grullon 、Dawei Yang、Charles A. Powell 、Mary Beth Beasley 、Jun Zhu 、Eric L. Snyder、Shaomin Li、Hideo Watanabe
  • Journal Title: bioRxiv Volume: －
  • DOI: 10.1101/2022.03.06.483161
  • Int'l Joint Research
• [Journal Article] Prototypical oncogene family Myc defines unappreciated distinct lineage states of small cell lung cancer (2021)
  • Author(s): Ayushi S. Patel、Seungyeul Yoo、Ranran Kong、Takashi Sato、Abhilasha Sinha、Sarah Karam、Li Bao、Maya Fridrikh、Katsura Emoto、German Nudelman、Charles A. Powell、Mary Beth Beasley、Jun Zhu、Hideo Watanabe
  • Journal Title: Science Advances Volume: 7 Issue: 5
  • DOI: 10.1126/sciadv.abc2578
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Standard therapy-resistant small cell lung cancer showing dynamic transition of neuroendocrine fate during the cancer trajectory: A case report (2021)
  • Author(s): Fumimaro Ito、Takashi Sato 、Katsura Emoto、Nobuki Kaizuka、Kazuma Yagi、Rinako Watanabe、Mizuha Haraguchi Hashiguchi 、Hironori Ninomiya、Yuki Ikematsu、Kentaro Tanaka、Hideharu Domoto、Tetsuya Shiomi
  • Journal Title: Molecular and Clinical Oncology Volume: 15 Issue: 6 Pages: 261-261
  • DOI: 10.3892/mco.2021.2423
  • Peer Reviewed
• [Presentation] Epigenomic profiling identifies distinct neuroendocrine subtypes in lung cancer with neuroendocrine differentiation (2022)
  • Author(s): Sato T, Hamamoto J, Emoto K, Fukushima T, Sugihara K, Shirasawa M, Nakahara Y, Igawa S, Murakumo Y, Kohno T, Shiraishi K, Yasuda H, Soejima K, Watanabe H. and Naoki K
  • Organizer: AACR Annual Meeting 2022
  • Int'l Joint Research
• [Presentation] Transcriptional circuitry of NKX2-1 and SOX1 defines a previously unrecognized lineage subtype of small cell lung cancer (2022)
  • Author(s): Kong R, Patel AS, Sato T, Yoo S, Sinha A, Tian Y, Jiang Y, Powell CA, Snyder E, Jiang J, Li S. and Watanabe H
  • Organizer: AACR Annual Meeting 2022
  • Int'l Joint Research
• [Presentation] Epigenomic profiling identifies distinct neuroendocrine subtypes in lung cancer with neuroendocrine differentiation (2022)
  • Author(s): Takashi Sato, Junko Hamamoto, Katsura Emoto, Takahiro Fukushima, Kai Sugihara, Masayuki Shirasawa, Yoshiro Nakahara, Satoshi Igawa, Yoshiki Murakumo, Takashi Kohno, Kouya Shiraishi, Hiroyuki Yasuda, Kenzo Soejima, Hideo Watanabe, Katsuhiko Naoki
  • Organizer: AACR Annual Meeting 2022
  • Int'l Joint Research
• [Presentation] 学会奨励賞受賞講演 肺癌細胞における分化系統プログラムの不均一性の解明 (2020)
  • Author(s): 佐藤崇
  • Organizer: 第60回日本呼吸器学会学術講演会
  • Invited