癌症转移依赖于细胞外基质附着的丧失和循环传播后的细胞存活。脱离癌细胞的聚集和抗氧化防御的增加可以增强转移性扩散。

通过描绘细胞聚集如何限制活性氧（ROS），研究人员将这些反应联系了起来。附着丧失导致线粒体波动和ROS产生的增加。细胞聚集的形成引起缺氧环境，其驱动缺氧诱导因子1-α（Hif1α）介导的线粒体自噬，从而清除受损的线粒体并限制ROS。然而，缺氧和线粒体功能的降低促进了对产生ATP的糖酵解的依赖，这由胞浆的氧化还原平衡所产生。阻止这种代谢适应或破坏细胞聚集会导致ROS积累、细胞死亡和体内转移能力的降低。这些结果为细胞聚集在促进细胞外基质分离和转移扩散期间存活中的作用提供了机制解释，并且找到一个可供靶向的弱点。

附：英文原文

Title: Cell Clustering Promotes a Metabolic Switch that Supports Metastatic Colonization

Author: Christiaan F. Labuschagne, Eric C. Cheung, Julianna Blagih, Marie-Charlotte Domart, Karen H. Vousden

Issue&Volume: 22 August 2019

Abstract: Cancer metastasis depends on cell survival following loss of extracellular matrix attachment and dissemination through the circulation. The metastatic spread can be enhanced by the clustering of detached cancer cells and increased antioxidant defense. Here, we link these responses by describing how cell clustering limits reactive oxygen species (ROS). Loss of attachment causes mitochondrial perturbations and increased ROS production. The formation of cell clusters induces a hypoxic environment that drives hypoxia-inducible factor 1-alpha (Hif1α)-mediated mitophagy, clearing damaged mitochondria and limiting ROS. However, hypoxia and reduced mitochondrial capacity promote dependence on glycolysis for ATP production that is supported by cytosolic reductive metabolism. Preventing this metabolic adaptation or disruption of cell clusters results in ROS accumulation, cell death, and a reduction of metastatic capacity in vivo. Our results provide a mechanistic explanation for the role of cell clustering in supporting survival during extracellular matrix detachment and metastatic spread and may point to targetable vulnerabilities.

DOI: https://doi.org/10.1016/j.cmet.2019.07.014

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30387-0#