Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, USA.
Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nat Cell Biol. 2023 Mar;25(3):415-424. doi: 10.1038/s41556-023-01092-1. Epub 2023 Feb 16.
Tissue fibrosis and extracellular matrix (ECM) stiffening promote tumour progression. The mechanisms by which ECM regulates its contacting cells have been extensively studied. However, how stiffness influences intercellular communications in the microenvironment for tumour progression remains unknown. Here we report that stiff ECM stimulates the release of exosomes from cancer cells. We delineate a molecular pathway that links stiff ECM to activation of Akt, which in turn promotes GTP loading to Rab8 that drives exosome secretion. We further show that exosomes generated from cells grown on stiff ECM effectively promote tumour growth. Proteomic analysis revealed that the Notch signalling pathway is activated in cells treated with exosomes derived from tumour cells grown on stiff ECM, consistent with our gene expression analysis of liver tissues from patients. Our study reveals a molecular mechanism that regulates exosome secretion and provides insight into how mechanical properties of the ECM control the tumour microenvironment for tumour growth.
组织纤维化和细胞外基质（ECM）变硬促进肿瘤进展。ECM 调节与其接触细胞的机制已得到广泛研究。然而，ECM 的硬度如何影响肿瘤进展微环境中的细胞间通讯尚不清楚。在这里，我们报告说，僵硬的 ECM 会刺激癌细胞释放外泌体。我们描绘了一条分子途径，该途径将僵硬的 ECM 与 Akt 的激活联系起来，Akt 又促进 GTP 加载到 Rab8，从而驱动外泌体的分泌。我们进一步表明，在硬 ECM 上生长的细胞产生的外泌体可有效促进肿瘤生长。蛋白质组学分析显示，在接受源自硬 ECM 上生长的肿瘤细胞的外泌体处理的细胞中，Notch 信号通路被激活，这与我们对患者肝组织的基因表达分析一致。我们的研究揭示了调节外泌体分泌的分子机制，并深入了解 ECM 的力学性质如何控制肿瘤生长的肿瘤微环境。
