Peptide-mediated inhibition of aberrant chaperone-mediated autophagy in pericytes prevents glioblastoma progression through MAPT/tau secretion
Abstract
Glioblastoma (GB) is the most aggressive brain cancer, with poor prognosis due to infiltrative invasion of glioma stem cells (GSCs) and the immunosuppressive tumor microenvironment (TME). We have previously demonstrated that pericytes (PCs), specialized cells in the blood microvessels surrounding GB, are conditioned by infiltrating tumor cells to aberrantly upregulate their chaperone-mediated autophagy (CMA). Elevated CMA in PCs promotes stable cell-cell interactions with tumor cells and a pro-tumoral immune phenotype that supports tumor progression. In this work, to test if inhibition of CMA in PCs might be an effective strategy to reduce tumor survival, we have used the phosphopeptide P140, known to restore aberrant CMA upregulation in specific immune cells. We found that administration of P140 peptide in an immunocompetent GB mouse model with both patient-derived GSCs and GB cell lines, neutralizes GB-induced PC CMA upregulation resulting in ablation of PC-tumor cell interactions and triggering of a secretome toxic to tumor cells. We identified MAPT/tau, a known CMA substrate, as one of the main components of this secretome, and discovered that CMA-dependent PC MAPT/tau secretion within the GB TME plays a key role in cancer progression and recurrence. Furthermore, we found that perivascular accumulation of MAPT/tau is an effective way to monitor peptide P140 treatment efficacy in GB and for prognosis of the patient evolution. Our findings validate P140 peptide treatment as a safe and specific strategy to halt GB progression and establish the clinical relevance of extracellular MAPT/tau as a biomarker for therapeutic success in GB.
Related
- MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression in mice
- Azithromycin Derivatives to Mitigate Off-Target Inhibition of Autophagy and Retain Beneficial Host Directed Effects
- Resistance-Mutant Rescue Establishes On-Target CHI3L1 Inhibition by CHI-DEL, a Brain-Penetrant Small Molecule with In Vivo Efficacy in Glioblastoma
- Complex I Inhibition Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance
- GABA signaling activation drives glioblastoma progression in female mice through myeloid-derived suppressor cells
BibTeX
@article{salinas2026peptidemediated,
title = {{Peptide-mediated inhibition of aberrant chaperone-mediated autophagy in pericytes prevents glioblastoma progression through MAPT/tau secretion}},
author = {Maria Dolores Salinas and Isabel Maria Martínez and Elena Naranjo and Maria Luisa Molina and Ana Maria Cuervo and Sylviane Muller and Rut Valdor},
journal = {Autophagy},
year = {2026},
month = may,
doi = {10.1080/15548627.2026.2672700},
url = {https://univoak.hal.science/hal-05758161v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Peptide-mediated inhibition of aberrant chaperone-mediated autophagy in pericytes prevents glioblastoma progression through MAPT/tau secretion
AU - Maria Dolores Salinas
AU - Isabel Maria Martínez
AU - Elena Naranjo
AU - Maria Luisa Molina
AU - Ana Maria Cuervo
AU - Sylviane Muller
AU - Rut Valdor
PY - 2026
DA - 2026/05/18
JO - Autophagy
DO - 10.1080/15548627.2026.2672700
UR - https://univoak.hal.science/hal-05758161v1
AB - Glioblastoma (GB) is the most aggressive brain cancer, with poor prognosis due to infiltrative invasion of glioma stem cells (GSCs) and the immunosuppressive tumor microenvironment (TME). We have previously demonstrated that pericytes (PCs), specialized cells in the blood microvessels surrounding GB, are conditioned by infiltrating tumor cells to aberrantly upregulate their chaperone-mediated autophagy (CMA). Elevated CMA in PCs promotes stable cell-cell interactions with tumor cells and a pro-tumoral immune phenotype that supports tumor progression. In this work, to test if inhibition of CMA in PCs might be an effective strategy to reduce tumor survival, we have used the phosphopeptide P140, known to restore aberrant CMA upregulation in specific immune cells. We found that administration of P140 peptide in an immunocompetent GB mouse model with both patient-derived GSCs and GB cell lines, neutralizes GB-induced PC CMA upregulation resulting in ablation of PC-tumor cell interactions and triggering of a secretome toxic to tumor cells. We identified MAPT/tau, a known CMA substrate, as one of the main components of this secretome, and discovered that CMA-dependent PC MAPT/tau secretion within the GB TME plays a key role in cancer progression and recurrence. Furthermore, we found that perivascular accumulation of MAPT/tau is an effective way to monitor peptide P140 treatment efficacy in GB and for prognosis of the patient evolution. Our findings validate P140 peptide treatment as a safe and specific strategy to halt GB progression and establish the clinical relevance of extracellular MAPT/tau as a biomarker for therapeutic success in GB.
SN - 1554-8627
SN - 1554-8635
ER -