The Randall Centre for Cell & Molecular Biophysics, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, School of Cancer and Pharmaceutical Sciences, King's College London, London, UK.
Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
Nat Commun. 2021 Dec 10;12(1):7180. doi: 10.1038/s41467-021-27513-z.
Metastasis is the main cause of carcinoma-related death, yet we know little about how it initiates due to our inability to visualize stochastic invasion events. Classical models suggest that cells accumulate mutations that first drive formation of a primary mass, and then downregulate epithelia-specific genes to cause invasion and metastasis. Here, using transparent zebrafish epidermis to model simple epithelia, we can directly image invasion. We find that KRas-transformation, implicated in early carcinogenesis steps, directly drives cell invasion by hijacking a process epithelia normally use to promote death-cell extrusion. Cells invading by basal cell extrusion simultaneously pinch off their apical epithelial determinants, endowing new plasticity. Following invasion, cells divide, enter the bloodstream, and differentiate into stromal, neuronal-like, and other cell types. Yet, only invading KRas cells deficient in p53 survive and form internal masses. Together, we demonstrate that KRas-transformation alone causes cell invasion and partial dedifferentiation, independently of mass formation.
转移是癌症相关死亡的主要原因，但由于我们无法可视化随机入侵事件，因此对其如何发生知之甚少。经典模型表明，细胞积累突变，首先驱动原发性肿块的形成，然后下调上皮特异性基因以引起侵袭和转移。在这里，我们使用透明的斑马鱼表皮来模拟简单的上皮组织，可以直接对其进行成像。我们发现，KRas 转化（涉及早期癌变步骤）通过劫持上皮细胞通常用来促进死亡细胞挤出的过程，直接驱动细胞入侵。通过基底细胞挤出进行入侵的细胞同时切断它们的顶端上皮决定因素，赋予新的可塑性。入侵后，细胞分裂，进入血液，并分化为基质细胞、神经元样细胞和其他细胞类型。然而，只有缺乏 p53 的侵袭性 KRas 细胞才能存活并形成内部肿块。总之，我们证明了 KRas 转化本身就会导致细胞侵袭和部分去分化，而与肿块形成无关。
