染色体不安定による非細胞自律がんの進行

Jun Li^1,2, Melissa J Hubisz^3,4,5,6, Ethan M Earlie^3,4,5

¹Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Nature

|August 23, 2023

まとめ

染色体不安定性 (CIN) は,cGAS- STING経路を活性化し,転移性腫瘍環境を作り出すことにより,癌の転移を促します. この経路への介入は,特に免疫能力のある環境では,転移を抑制します.

科学分野:

腫瘍学
免疫学
遺伝学

背景:

染色体不安定性 (CIN) は,癌の転移の要因として知られている.
CINによる転移における免疫系の役割は完全に理解されていません.

研究の目的:

CINによるcGAS-STING経路の慢性的な活性化が腫瘍の微小環境と転移にどのように影響するかを調査する.
cGAS-STING経路を標的とした治療戦略を研究する.

主な方法:

単細胞のトランスクリプトミックのデータから細胞間の相互作用を分析するための新しいツールであるコンタクトトレーシングを使用した.
cGAS- STING経路の活性化,インターフェロン反応,および内 плазма網膜 (ER) ストレスを含む,癌細胞におけるCIN誘発信号の研究.
CINの逆転,STINGの減少,およびERのストレス抑制が免疫能力のあるモデルおよび免疫能力の低下したモデルにおける転移への影響を評価した.
メラノーマ,乳がん,大腸がんの臨床前モデルで評価されたSTING阻害剤.
CIN,cGAS活性化,ERストレス,転移との関連性について,ヒトのトリプルネガティブ乳がん (TNBC) を分析した.

主要な成果:

CIN誘発によるcGAS- STINGの活性化により,がん細胞のシグナル再配線が起こり,転移を促す腫瘍の微環境が形成されます.
この再配線は,STINGの下流のタイプIインターフェロンタキフィラキスを含み,ERのストレスを増加させます.
CINを逆転させ,STINGを抑制したり,ERストレスを阻害したりすることで,CINに依存する転移前効果を無効化し,免疫能力のある環境で転移を抑制します.
STING阻害剤は,腫瘍細胞内にあるSTINGに依存する様々な癌のCIN誘発性転移を効果的に抑制する.
人間のTNBCにおけるCINとcGASの活性化は,ERストレス,免疫抑制,転移と相関する.

結論:

cGAS- STING経路と,その後のERストレスは,CIN主導の転移の重要なメディエーターです.
腫瘍細胞に内在するSTINGを標的とした治療は CINが誘発する癌に対する有望な治療戦略です
CIN誘発の炎症と関連するERストレスは,特にTNBCでは転移と免疫抑制の重要な要因です.

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