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コレステロールオックストロフィックリンパ腫におけるスクアレン蓄積は,酸化性細胞死を防ぐ

Javier Garcia-Bermudez¹, Lou Baudrier¹, Erol Can Bayraktar¹

¹Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA.

|February 15, 2019

まとめ

ALK陽性のアナプラスティック大細胞リンパ腫 (ALCL) のような特定の癌は,コレステロールを産生することができず,それを輸入しなければなりません. このコレステロール依存性つまりオクストロフィーはこれらの特定の癌の治療対象となる可能性があります

科学分野:

生物化学
細胞生物学
腫瘍学

背景:

コレステロールは細胞の成長と増殖に不可欠です.
哺乳類の細胞は,吸収または新合成によってコレステロールを取得します.
がん細胞がコレステロール経路に依存しているかどうかは完全に解明されていません

研究の目的:

コレステロールにオックストロフィックな癌細胞のタイプを特定する.
コレステロールオクストロフィーの分子基礎を決定する.
癌におけるコレステロール代謝を標的とした治療戦略を探求する.

主な方法:

DNAバーコード細胞系による競争性増殖測定法
メタボリック遺伝子発現分析
CRISPRベースの遺伝子スクリーニングです
ALK陽性アナプラスティック大細胞リンパ腫 (ALCL) 細胞系と腫瘍の分析

主要な成果:

コレステロールの吸収に依存する腫瘍細胞のサブセットを特定しました
スクアレンモノオキシゲナーゼの喪失は,特にALK+ALCLではコレステロールオキシトロフィーを引き起こします.
ALK+ALCLにおけるスクアレン蓄積は,脂質プロフィールを変化させ,フェロプトーシスから保護する.
低密度脂質タンパク質受容体媒介によるコレステロールの吸収は,ALCLの成長に不可欠です.

結論:

ALK+ALCLにおけるコレステロールオクストロフィーは,標的となる脆弱性です.
スクアレン蓄積は,ALCL細胞に成長の利点を与える.
体系的なアプローチにより特定の癌の独特の栄養依存性を発見できます

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