MLL1调节细胞因子驱动的细胞迁移和转移
Praful R Nair1, Ludmila Danilova2, Estibaliz Gómez-de-Mariscal3,4
1Institute for Nanobiotechnology, The Johns Hopkins University, Baltimore, MD 21218, USA.
Science advances
|March 13, 2024
概括
组织素甲基转移酶混合血统白血病1 (MLL1) 通过控制细胞因子分泌和细胞力学来驱动癌细胞迁移和转移. 向MLL1显著减少瘤生长和转移,为转移性疾病提供潜在的治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- 细胞迁移是转移的关键驱动因素,这一过程传统上与免疫细胞的细胞因子产生有关.
- 癌细胞内在细胞因子在迁移和转移中的作用仍然不太清楚.
研究的目的:
- 为了研究基因组甲基转移酶混合血统白血病1 (MLL1) 在调节癌细胞迁移和转移中的作用.
- 阐明MLL1控制细胞迁移和增殖的分子机制.
主要方法:
- 在小鼠的 ортотоп瘤模型中利用MLL1枯竭.
- 分析了细胞因子分泌 (IL-6,IL-8,TGF-β1) 和下游信号通路 (例如,pSTAT3,Gli2,ROCK1/2,PMLC2).
- 评估了actin光纤组合,肌缩性和动态突起生成.
主要成果:
- MLL1通过分泌的细胞因子IL-6,IL-8和TGF-β1控制3D细胞迁移,通过特定的分子轴作用.
- MLL1调节了动因动态和肌缩性,这对细胞迁移和突起形成至关重要.
- 在瘤中,MLL1的枯竭减少了肺转移负担,并改善了生存率,独立于原发性瘤生长率.
- 与MLL1-Menin抑制剂和帕克利塔塞尔的联合治疗有效地减少了瘤生长并消除了现有的转移.
结论:
- MLL1是癌细胞迁移和转移的关键调节者,通过内在细胞因子产生和细胞骨控制起作用.
- 向MLL1,特别是在组合治疗中,是治疗转移性癌症的有希望的策略.
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