2023 Fiscal Year Final Research Report

Unraveling tumor phenotypic heterogeneity by single-cell epigenetic profiling

Research Project

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Project/Area Number	20KK0184
Research Category	Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
Allocation Type	Multi-year Fund
Review Section	Medium-sized Section 50:Oncology and related fields
Research Institution	Nagoya University
Principal Investigator	Hinohara Kunihiko 名古屋大学, 医学系研究科, 特任准教授 (50549467)
Co-Investigator(Kenkyū-buntansha)	小嶋泰弘名古屋大学, 医学系研究科, 特任講師 (00881731) 加藤真一郎名古屋大学, 医学系研究科, 助教 (40751417)
Project Period (FY)	2020-10-27 – 2024-03-31
Keywords	エピゲノム / ARID2 / SWI/SNF / 乳がん / メラノーマ
Outline of Final Research Achievements	In this study, melanoma and breast cancer, in which ARID2 mutations frequently occur at the onset (early stage) and recurrence (late stage), were used as models for analysis, and their molecular profiles were analyzed multimodally, including single-cell and interactome analysis. The results showed that ARID2 mutations cause disassembly of the PBAF complex and dissociation of RUNX3 binding, resulting in a predominance of ARID1A-containing BAF complexes in the gene expression regulatory regions, which in turn maintains cell proliferative potential. Using this experimental model established in this study, we will continue to analyze the downstream molecular mechanisms in detail in order to discover molecules that can be used as therapeutic targets for ARID2 mutant cancers.
Free Research Field	腫瘍生物学
Academic Significance and Societal Importance of the Research Achievements	多くのがん種で高頻度に変異を認めるARID2変異だが、がんの悪性化進展や薬剤耐性化機構においてどのような働きを持つのか未だ不明な部分が多い。現時点でARID2の不活化変異の標的化は技術的に困難であることから、ARID2変異がもたらす下流の分子的変化の解明から標的化し得る分子を同定することが必要である。今回の研究成果として、ARID2変異を解析する実験モデルを確立し、顕著な変化を示す複数のタンパク質の情報を得ることができた。今後これらのメカニズムをさらに研究し、治療標的となる因子の発見につなげていく。