Chaperone-Mediated Autophagy Ablation in Pericytes Reveals New Glioblastoma Prognostic Markers and Efficient Treatment Against Tumor Progression

Abstract

Background: The lack of knowledge of the progression mechanisms of glioblastoma (GB), the most aggressive brain tumor, contributes to the absence of successful therapeutic strategies. Our team has recently demonstrated a crucial new role for chaperone-mediated autophagy (CMA) in pericytes (PC)-acquired immunosuppressive function, which prevents anti-tumor immune responses and facilitates GB progression. The possible impact that GB-induced CMA in PC has on other functions that might be useful for future GB prognosis/treatment, has not been explored yet. Thus, we proposed to analyze the contribution of CMA to other GB-induced changes in PC biology and determine if CMA ablation in PC is a key target mechanism for GB treatment.Methods: Studies of RNA-seq and secretome analysis were done in GB-conditioned PC with and without CMA (from knockout mice for LAMP-2A) and compared to control PC. Different therapeutic strategies in a GB mouse model were compared.Results: We found several gene expression pathways enriched in LAMP2A-KO PC and affected by GB-induced CMA in PC that correlate with our previous findings. Phagosome formation, cellular senescence, focal adhesion and the effector function to promote anti-tumor immune responses were the most affected pathways, revealing a transcriptomic profiling of specific target functions useful for future therapies. In addition, several molecules associated with tumor mechanisms and related to tumor immune responses such as gelsolin, periostin, osteopontin, lumican and vitamin D, were identified in the PC secretome dependent on GB-induced CMA. The CMA ablation in PC with GB cells showed an expected immunogenic phenotype able to phagocyte GB cells and a key strategy to develop future therapeutic strategies against GB tumor progression. A novel intravenous therapy using exofucosylated CMA-deficient PC was efficient to make PC reach the tumor niche and facilitate tumor elimination.Conclusion: Our results corroborate previous findings on the impaired immunogenic function of PC with GB-induced CMA, driving to other altered PC functions and the identifications of new target markers related to the tumor immune responses and useful for GB prognosis/therapy. Our work demonstrates CMA ablation in PC as a key target mechanism to develop a successful therapy against GB progression.

Chaperone-Mediated Autophagy in Pericytes: A Key Target for the Development of New Treatments against Glioblastoma Progression

“…Thus far, PCs might be considered as tumor attackers, but GB cells can manipulate PC functions, changing their phenotype to promote pro-tumoral instead of anti-tumoral immune responses [ 17 , 39 , 53 , 54 ]. Thus, a detailed dissection and a better understanding of the role of CMA in PCs in a healthy brain versus those located in the tumor microenvironment is necessary to develop therapies to counter GB progression mediated by CMA-driven PCs.…”

“…In recent years, GB environment and implicated cells and molecules have acquired a special interest. In particular, peritumoral PCs are an attractive target to generate new therapeutical approaches because they are located in small blood vessels of the brain parenchyma, where GB spreads and invades the perivascular space [ 17 , 39 ].…”

“…A transient ROS burst is produced in the PCs following physical interaction with the GB cell, leading to overexpression of LAMP-2A, the only limiting molecule for CMA activity ( Figure 2 ). CMA is then aberrantly upregulated in PCs, consequently affecting the PC phenotype, which promotes stable cell-to-cell interactions that favor tumor cell proliferation, and which induces an immunosuppressive function that impairs anti-tumor immune responses [ 17 , 39 ].…”

“…Importantly, data from our lab have shown that, in addition to upregulation of LAMP-2A expression and, therefore, increased CMA activity in tumor cells, GB-mediated upregulation of CMA in PCs is also required for tumor growth [ 17 ]. Thus, in GB, LAMP-2A has been considered a potential prognosis marker in tumorigenicity [ 38 ] as well as a predictor of poor cancer prognosis due to the tumor cell infiltration and progression driven by tumor cell–PC interactions [ 17 , 39 ].…”

Role of Chaperone-Mediated Autophagy in Ageing Biology and Rejuvenation of Stem Cells

“…Glioma tumour cells have been shown to induce CMA upregulation in surrounding pericytes thus suppressing their antitumour function and inducing immunotolerance to cancer ( Valdor et al, 2019 ; Molina et al, 2022 ). In detail, tumour-induced aberrant upregulation of CMA in pericytes causes an anti-inflammatory phenotype that prevents T cell activation for tumour clearance.…”