PHGDHの異質性は,がん細胞の拡散と転移を強める

Matteo Rossi^1,2, Patricia Altea-Manzano^1,2, Margherita Demicco^1,2

¹Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium.

Nature

|May 18, 2022

まとめ

低リン酸脱水素酶 (PHGDH) 発現は,タンパク質の糖化を変化させることで癌の転移を促進する. この発見は,腫瘍の攻撃性のマーカーであり,潜在的な治療標的としてのPHGDHの異質性を明らかにする.

科学分野:

腫瘍学
癌生物学
代謝経路

背景:

癌の転移は細胞の拡散と臓器の播種を含む複雑なプロセスです
遺伝的,転写的,転写的,代謝的異質性は癌の進行に影響する.
代謝異質性,特にフォスフォグリセラート脱水素酵素 (PHGDH) の転移における特定の役割は十分に研究されていない.

研究の目的:

癌の転移におけるフォスフォグリセラート脱水素酶 (PHGDH) の役割を調査する.
PHGDHが腫瘍の拡散と遠方の病変の形成に影響を与えるメカニズムを解明する.

主な方法:

原発性乳がんにおけるPHGDH発現の分析と患者の生存率との相関
マウスモデルを用いた体内試験で,PHGDHの静止が転移に与える影響を評価した.
PHGDHとフォスフォフルトキナーゼの分子相互作用の調査.
ヘクソアミン-シアル酸経路とタンパク質の糖化,特にインテグリン αvβ3の糖化に関する評価.

主要な成果:

主要腫瘍における異質的または低PHGDH発現は,乳がん患者の転移フリー生存率の低下と相関する.
PHGDHの低循環腫瘍細胞と早期転移病変はマウスモデルで濃縮されています.
主要な腫瘍のPHGDHを静止すると,転移の形成が促進されます.
フォスフォフルトキナーゼとのPHGDH相互作用の喪失は,ヘキソアミン- シアリック酸経路を活性化させ,異常なタンパク質グリコシレーションとインテグリンαvβ3シアライレーションを増加させます.
シアリレーションの阻害は,PHGDHが低いがん細胞のプロメタスタティックなフェノタイプを逆転させます.

結論:

低PHGDH発現は,その触媒活動とは関係なく,がん細胞の拡散と転移を強める.
主要腫瘍におけるPHGDHの異質性は,腫瘍の攻撃性の指標として機能する.
低PHGDH発現のがんにおける転移の管理のための治療戦略は,シアリレーションをターゲットにすることが可能である.

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