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A novel patient-derived pancreatic acinar cell carcinoma cell line shows high sensitivity to bortezomib

星, 大輔 東京大学 DOI:10.15083/0002006952

2023.03.24

概要

[課程-2]
審査の結果の要旨
氏名星 大輔
膵腺房細胞癌は希少な癌であり、既存の細胞株の報告は 3 例のみであると共に、いずれ
も腺房細胞としての性質の検討は不十分である。本研究は膵腺房細胞癌の 1 症例からオル
ガノイド培養法を用いて新規オルガノイド細胞株の樹立と治療候補薬剤の探索を含む特徴
付けを試みたものであり、下記の結果を得ている。
1.

膵腺房細胞癌の 1 症例の胆汁検体、生検検体、手術検体のそれぞれに対しオルガノイ
ド培養を試み、オルガノイドを樹立した。その中で生検検体に由来するオルガノイド
をヌードマウス皮下に移植する事でゼノグラフトを得た。このゼノグラフトに対し再
度オルガノイド培養を試みる事で、凍結・解凍および半年を超える長期培養が可能な
オルガノイド細胞株を得た。このオルガノイド細胞株について、免疫染色を含む組織
像の検討および免疫ブロットによって膵腺房細胞癌の性質を有している事を確認し
た。また、次世代シーケンサーによる変異や LOH の解析、アレイ CGH による検討
からも原発巣および PACC の性質を維持している事を確認した。

2.

上記の変異解析の際、原発巣に CDKN2A の (chr9:21974701) 9 塩基欠失
c.117_125delCGCACCGAA (p. Ala40_Asn42del)、 ATRX の (chrX:76939056) 1 塩基欠失
c.1691delA (p.Asn564fs)を認め、ATRX の 1 塩基欠失は得られたオルガノイド細胞株で
も保持されていた。これらの変異は近接した領域で類似の変異の報告が多数あり、ド
ライバー変異である可能性が示唆された。

3.

得られたオルガノイド細胞株に対して 364 種の薬剤によるスクリーニングを行い、単
剤での確認を経て、ボルテゾミブ、バフィロマイシン A1 がこの細胞株に著効する事
を見出した。

4.

この細胞株に対するレンチウイルスベクターによる遺伝子導入が容易な事を示した。
また、導管細胞のマーカーで癌幹細胞マーカーでもある CD133 の強制発現が、この
細胞株の分化やヌードマウス皮下での腫瘍形成能に明らかな影響を与えない事を示し
た。
以上、本論文は新規ヒト膵腺房細胞癌オルガノイド細胞株の樹立と、その解析結果につ

いて報告した。本研究は未解明な部分の多い膵腺房細胞癌に対する知見を深めると共に、
腫瘍の本態解明や新規治療薬の開発にも資すると考えられる。
よって本論文は博士( 医学 )の学位請求論文として合格と認められる。

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