ABSTRACT

Microtubules (MTs) control cell shape and intracellular cargo transport. The role of MT turnover in the migration of slow-moving cells through endothelial barriers remains unclear. To irreversibly interfere with MT disassembly, we have used the MT-stabilizing agent zampanolide (ZMP) in Β16F10 melanoma as amodel of slow-moving cells. ZMP-treated B16 cells failed to follow chemotactic gradients across rigid confinements and could not generate stable sub-endothelial pseudopodia under endothelial monolayers. In vivo, ZMP-treated Β16 cells failed to extravasate though lung capillaries. In contrast to melanoma cells, the chemotaxis and transendothelial migration of ZMP-treated Tcells were largely conserved. This is afirst demonstration that MT disassembly is akey checkpoint in the directional migration of cancer cells but not of lymphocytes.

摘要

微管 (MT) 控制细胞形状和细胞内货物运输。MT 周转在缓慢移动的细胞通过内皮屏障迁移中的作用仍不清楚。为了不可逆地干扰 MT 分解，我们在 Β16F10 黑色素瘤中使用了 MT 稳定剂赞帕内酯 (ZMP) 作为缓慢移动细胞的模型。ZMP 处理的 B16 细胞未能遵循刚性限制的趋化梯度，并且无法在内皮单层下产生稳定的内皮下伪足。在体内，ZMP 处理的 Β16 细胞未能通过肺毛细血管外渗。与黑色素瘤细胞相比，ZMP 处理的 T 细胞的趋化性和跨内皮迁移在很大程度上是保守的。这是首次证明 MT 分解是癌细胞定向迁移的关键检查点，但不是淋巴细胞定向迁移的检查点。