Peptide-mediated inhibition of aberrant chaperone-mediated autophagy in pericytes prevents glioblastoma progression through MAPT/tau secretion

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.Abbreviations: ACTA2/ASMA: actin alpha 2, smooth muscle; BBB: blood-brain barrier; CMA: chaperone-mediated autophagy; CTLA4: cytotoxic T-lymphocyte associated protein 4; DAB: 3–3′diaminobenzidine; GB: glioblastoma; GBCPC: GB-conditioned pericyte; GSCs: glioblastoma stem cells; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosome associated membrane protein 2A; LI: lysosomal inhibitors; MAPT/tau: microtubule associated protein tau; NAc: N-acetylcysteine; PC: pericyte; PCGB: pericyte-glioblastoma coculture; PDGFRB: platelet derived growth factor receptor beta; ROS: Reactive oxygen species; SPARC: secreted protein acidic and cysteine rich; TME: tumor microenvironment; TNT: tunneling nanotubes