Mechanical signals from the tumor microenvironment modulate cell mechanics and influence cell metabolism to promote cancer aggressiveness. Cells withstand external forces by adjusting the stiffness of their cytoskeleton. Microtubules (MTs) act as compression-bearing elements. Yet how cancer cells regulate MT dynamic in response to the locally constrained environment has remained unclear. Using breast cancer as a model of a disease in which mechanical signaling promotes disease progression, we show that matrix stiffening rewires glutamine metabolism to promote MT glutamylation and force MT stabilization, thereby promoting cell invasion. Pharmacologic inhibition of glutamine metabolism decreased MT glutamylation and affected their mechanical stabilization. Similarly, decreased MT glutamylation by overexpressing tubulin mutants lacking glutamylation site(s) decreased MT stability, thereby hampering cancer aggressiveness in vitro and in vivo. Together, our results decipher part of the enigmatic tubulin code that coordinates the fine-tunable properties of MT and link cell metabolism to MT dynamics and cancer aggressiveness.

来自肿瘤微环境的机械信号调节细胞力学并影响细胞代谢以促进癌症侵袭性。细胞通过调整其细胞骨架的刚度来承受外力。微管 (MT) 充当承压元件。然而，癌细胞如何响应局部受限的环境来调节 MT 动态仍不清楚。使用乳腺癌作为机械信号促进疾病进展的疾病模型，我们表明基质硬化重新连接谷氨酰胺代谢以促进 MT 谷氨酰化并迫使 MT 稳定，从而促进细胞侵袭。谷氨酰胺代谢的药理学抑制降低了 MT 谷氨酰化并影响了它们的机械稳定性。相似地，体外和体内。总之，我们的结果破译了部分神秘的微管蛋白代码，该代码协调 MT 的微调特性，并将细胞代谢与 MT 动力学和癌症侵袭性联系起来。