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 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.
Authors
- Neuza Domingues
- Nuno Raimundo
- Pedro A. Dionísio (ORCID: https://orcid.org/0000-0003-2756-1863)
- Eric Chevet
- Philippe Bun (ORCID: https://orcid.org/0000-0002-7975-1768)
- Céline Keime (ORCID: https://orcid.org/0000-0001-7604-3814)
- Raphaël Pineau (ORCID: https://orcid.org/0000-0002-0701-7302)
- Béatrice Cholley
- Quentin Lemercier
- Sofia Roque Freire (ORCID: https://orcid.org/0009-0002-2316-1096)
- Ida Chiara Guerrera
- Joanna Lipecka (ORCID: https://orcid.org/0000-0003-0000-2666)
- Cédric Delevoye
- Lydia Danglot
- Somya Vats
- Jose Wojnacki
- Ludivine Therreau
- Diana Zala
- Jean-Baptiste Moog
- Thierry Galli
Institutions
- Centre National de la Recherche Scientifique (FR)
- Pennsylvania State University (US)
- Inserm (FR)
- Université Paris Cité (FR)
- Université Paris Sciences et Lettres (FR)
- Sorbonne Université (FR)
- Institut Necker Enfants Malades (FR)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Oncogenesis Stress Signaling (FR)
- Centre Eugène Marquis (FR)
- Institut de Psychiatrie et Neurosciences de Paris (FR)
- FHU Neurovasc (FR)
- Biologie cellulaire et Cancer (FR)
- Structure fédérative de recherche Necker (FR)
- Université de Strasbourg (FR)
- University of Coimbra (PT)
- Penn State Milton S. Hershey Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-21
- DOI
- https://doi.org/10.1038/s41467-026-69900-4
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 0.00