Under conditions of starvation, normal and tumor epithelial cells can rewire their metabolism toward the consumption of extracellular proteins, including extracellular matrix-derived components as nutrient sources. The mechanism of pericellular matrix degradation by starved cells has been largely overlooked. Here it is shown that matrix degradation by breast and pancreatic tumor cells and patient-derived xenograft explants increases by one order of magnitude upon amino acid and growth factor deprivation. In addition, it is found that collagenolysis requires the invadopodia components, TKS5, and the transmembrane metalloproteinase, MT1-MMP, which are key to the tumor invasion program. Increased collagenolysis is controlled by mTOR repression upon nutrient depletion or pharmacological inhibition by rapamycin. The results reveal that starvation hampers clathrin-mediated endocytosis, resulting in MT1-MMP accumulation in arrested clathrin-coated pits. The study uncovers a new mechanism whereby mTOR repression in starved cells leads to the repurposing of abundant plasma membrane clathrin-coated pits into robust ECM-degradative assemblies.

中文翻译：

---

响应氨基酸饥饿的 mTOR 抑制通过 MT1-MMP 内吞作用停止促进 ECM 降解

在饥饿的情况下，正常和肿瘤上皮细胞可以将它们的新陈代谢重新连接到细胞外蛋白质的消耗，包括细胞外基质衍生成分作为营养来源。饥饿细胞导致细胞周围基质降解的机制在很大程度上被忽视了。此处显示，在氨基酸和生长因子剥夺后，乳腺和胰腺肿瘤细胞和患者来源的异种移植外植体的基质降解增加了一个数量级。此外，发现胶原分解需要侵袭伪足成分 TKS5 和跨膜金属蛋白酶 MT1-MMP，它们是肿瘤侵袭程序的关键。增加的胶原分解受养分耗尽后的 mTOR 抑制或雷帕霉素的药理学抑制所控制。结果表明，饥饿阻碍了网格蛋白介导的内吞作用，导致 MT1-MMP 在停滞的网格蛋白包被的凹坑中积累。该研究揭示了一种新机制，即饥饿细胞中的 mTOR 抑制导致大量质膜网格蛋白包被的凹坑重新用于强大的 ECM 降解组件。