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

TL;DR

This study shows that the protein VAMP7 helps cells release ER and mitochondrial proteins, which affects tumor development and immune cell activity in cancer.

Contribution

The study reveals VAMP7-dependent late endosomal secretion as an organelle quality-control and stress-communication mechanism in cancer.

Findings

VAMP7 knockout cells show impaired secretion of ER and mitochondrial proteins and signs of stress.

Pharmacological stress enhances VAMP7-dependent secretion.

VAMP7 knockout glioblastoma cells form more necrotic tumors with reduced macrophage infiltration.

Abstract

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 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.

The SNARE VAMP7 is essential for an unconventional secretory pathway based on late endosomal secretion. Here the authors show that this secretion functions as an organelle quality-control and stress-communication mechanism, with a particular relevance to cancer.

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