组织纤维化和细胞外基质（ECM）硬化促进肿瘤发展。 ECM 调节其接触的细胞的机制已广泛研究。然而，ECM 的硬度如何影响肿瘤微环境中的细胞间通信仍不清楚。在这里，我们报告 ECM 的硬度刺激癌细胞释放外泌体。我们描绘了一个分子途径，将硬 ECM 与 Akt 的激活联系起来，后者又促进 GTP 加载到驱动外泌体分泌的 Rab8。我们进一步展示，从生长在硬 ECM 上的细胞中产生的外泌体有效地促进肿瘤生长。蛋白质组学分析显示，在处理了源自生长在硬 ECM 上的肿瘤细胞的外泌体的细胞中，Notch 信号通路被激活，这与我们对来自患者肝组织的基因表达分析一致。我们的研究揭示了一个调节外泌体分泌的分子机制，并提供了关于 ECM 的机械特性如何控制肿瘤微环境以促进肿瘤生长的见解。 © 2023 年。作者在 Springer Nature Limited 独家许可下。

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.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.