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.

多种癌症相关基因既促进又矛盾地抑制生长起始，具体取决于细胞环境。我们发现了一种基于不对称细胞分裂的蛋白质 Stat3 发生这种情况的解释。在这里，我们展示了 Stathmin/PLK-1 的 Stat3 调节有丝分裂纺锤体方向，我们用它来创建和测试差异生长起始的模型。我们证明整合素-α6 是极化的并且是乳腺生长启动所必需的。纺锤体相对于极性整合素α6定向，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整合素α6遗传。 Stat3 抑制使纺锤体方向随机化，从而促进正常生长起始，同时减少肿瘤源性生长起始。脂筏破坏使整合素 α6 去极化，诱导纺锤体方向独立的整合素 α6 遗传。 Stat3 抑制不再影响这些细胞的生长，表明 Stat3 通过调节纺锤体方向来控制生长起始。