VAMP7-dependent late endosomal secretion of ER and mitochondrial proteins impacts the tumor microenvironment and macrophage engagement

Late endosomal secretion is an unconventional secretion mechanism that depends on the SNARE protein VAMP7. We previously showed that VAMP7 mediates the secretion of the ER protein Reticulon3. However, the functional relevance and molecular mechanism of this secretory pathway remain unclear. Here, we show that VAMP7 knockout cells exhibit impaired secretion of ER- and mitochondrial-derived proteins and signs of ER and mitochondrial stress. In addition, pharmacological induction of organellar stress enhances the VAMP7-dependent secretion. We assess the pathophysiological significance of this mechanism using a preclinical glioblastoma model. VAMP7 knockout glioblastoma cells implanted in male rat brain develop into larger, more necrotic tumors with reduced macrophage infiltration compared to controls, suggesting that VAMP7-dependent late endosomal secretion contributes to the tumor microenvironment and affects macrophage infiltration. Together, our results support a model in which late endosomal secretion functions as an organelle quality-control and stress-communication mechanism, with particular relevance to cancer.晚期内体分泌（late endosomal secretion）是一类依赖SNARE蛋白VAMP7的非常规分泌机制。我们既往研究证实，VAMP7可介导内质网（endoplasmic reticulum, ER）蛋白网蛋白3（Reticulon3）的分泌过程。然而，该分泌通路的功能相关性与分子机制至今仍未明确。本研究中，我们发现VAMP7基因敲除细胞存在内质网与线粒体来源蛋白的分泌受损现象，并表现出内质网与线粒体应激的特征。此外，药物诱导细胞器应激可增强VAMP7依赖的分泌过程。我们借助临床前胶质母细胞瘤模型评估了该机制的病理生理学意义：相较于对照组，植入雄性大鼠脑内的VAMP7基因敲除胶质母细胞瘤细胞可形成体积更大、坏死程度更高的肿瘤，且巨噬细胞浸润程度显著降低。上述结果提示，VAMP7依赖的晚期内体分泌可参与塑造肿瘤微环境并调控巨噬细胞浸润。综上，本研究结果支持如下模型：晚期内体分泌作为一种细胞器质量控制与应激通讯机制发挥功能，在癌症进程中具有尤为重要的意义。