Microtubule destabilization is a critical checkpoint of chemotaxis and transendothelial migration in melanoma cells but not in T cells

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.

微管（Microtubules, MTs）可调控细胞形态与胞内货物运输。目前学界对于微管周转在慢速迁移细胞穿越内皮屏障过程中的作用仍不明确。为实现对微管解聚的不可逆干预，我们以慢速迁移细胞模型——B16F10黑色素瘤细胞为研究对象，使用微管稳定剂扎那诺利德（zampanolide, ZMP）进行处理。经ZMP处理的B16细胞无法沿趋化梯度穿越刚性受限微环境，亦无法在内皮单层下方形成稳定的内皮下伪足。在体实验中，经ZMP处理的B16细胞无法完成肺毛细血管的外渗过程。与黑色素瘤细胞不同，经ZMP处理的T细胞的趋化活性与跨内皮迁移能力基本得以保留。本研究首次证实，微管解聚是癌细胞定向迁移的关键检查点，而对淋巴细胞的定向迁移无此调控作用。