Department of Integrative Oncology, BC Cancer Research Centre, BC Cancer Agency, Vancouver, BC, Canada; Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital, Vancouver, BC, Canada.
Department of Integrative Oncology, BC Cancer Research Centre, BC Cancer Agency, Vancouver, BC, Canada.
Cell Rep. 2020 Mar 17;30(11):3605-3615.e5. doi: 10.1016/j.celrep.2020.02.079.
Multiple cancer-related genes both promote and paradoxically suppress growth initiation, depending on the cell context. We discover an explanation for how this occurs for one such protein, Stat3, based on asymmetric cell division. Here, we show that Stat3, by Stathmin/PLK-1, regulates mitotic spindle orientation, and we use it to create and test a model for differential growth initiation. We demonstrate that Integrin-α6 is polarized and required for mammary growth initiation. Spindles orient relative to polar Integrin-α6, dividing perpendicularly in normal cells and parallel in tumor-derived cells, resulting in asymmetric or symmetric Integrin-α6 inheritance, respectively. Stat3 inhibition randomizes spindle orientation, which promotes normal growth initiation while reducing tumor-derived growth initiation. Lipid raft disruption depolarizes Integrin-α6, inducing spindle-orientation-independent Integrin-α6 inheritance. Stat3 inhibition no longer affects the growth of these cells, suggesting Stat3 acts through the regulation of spindle orientation to control growth initiation.
多种与癌症相关的基因既能促进又能反常地抑制生长起始，具体取决于细胞环境。我们发现了一种解释这种现象如何发生的方法，这种方法基于不对称细胞分裂。在这里，我们表明 Stat3 通过 Stathmin/PLK-1 调节有丝分裂纺锤体的取向，我们利用它来创建和测试一个用于差异化生长起始的模型。我们证明 Integrin-α6 是极化的，并且是乳腺生长起始所必需的。纺锤体相对于极性 Integrin-α6 取向，在正常细胞中垂直分裂，在肿瘤衍生细胞中平行分裂，分别导致不对称或对称的 Integrin-α6 遗传。Stat3 抑制使纺锤体取向随机化，这促进了正常的生长起始，同时减少了肿瘤衍生的生长起始。脂筏破坏使 Integrin-α6 去极化，诱导与纺锤体取向无关的 Integrin-α6 遗传。Stat3 抑制不再影响这些细胞的生长，这表明 Stat3 通过调节纺锤体取向来控制生长起始。
