クリプト密度と採用された増強剤は,腸腫瘍の発症の基礎となっている

Liam Gaynor^1,2, Harshabad Singh^1,3, Guodong Tie¹

¹Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.

Nature

|January 8, 2025

まとめ

結腸癌のアデノマには Apc 変異だけでなく隣接する変異した腸の暗号が必要ですこれらの協力する細胞の特定の増強剤のアクセシビリティは,早期の腫瘍発症を促します.

科学分野:

胃腸内科
癌生物学
遺伝学

背景:

Apcのような腫瘍性変異は大腸がんが発症するずっと前に健康な腸に存在します
Apc変異はWntシグナリングを活性化し,腸の幹細胞 (ISC) に成長の利点を与えます.
異なる起源のISCが同等に腫瘍を形成するか,または cis- 調節要素が腫瘍形成中にどのように変化するかについては不明である.

研究の目的:

無傷な腸でアデノマが形成されるのに,Apc変異だけでは十分かどうか調べる.
変異した腸の密室がアデノマの発生に与える影響を調べる
Wntの過剰活性化と腫瘍の進行に対するシス調節要素の調節を調査する.

主な方法:

腸の幹細胞のAPC消去を研究するために2つのマウスモデルを使用した.
アデノマ形成に対する暗号密度と集積の影響を評価した.
ATAC-seqを用いて,アデノマ関連および無関連のApc変異性ISCにおける強化剤におけるクロマチンのアクセシビリティを分析した.

主要な成果:

アデノマの形成は,APCの消去の必須の結果ではなかったが,変異した腸の密室の近くに必要だった.
密度の低下はアデノマの形成を阻害し,突然変異の密度が増加した.
アデノマに宿るISCは,アデノマを形成しないApc-nullISCとは異なり,数千の強化剤でオープンクロマチンを示した.

結論:

隣接する突然変異の腸内密室の協力は早期の結腸直腸腫瘍形成に不可欠です
特定の増強剤へのアクセシビリティの向上は,アデノマ発現における重要な出来事であり,アデノマ選択遺伝子の活性化を可能にします.
これらの増強剤の変化は,他の腫瘍性変異が蓄積するにつれて持続し,初期の役割を強調します.

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