Chaperone-Mediated Autophagy Controls Proteomic and Transcriptomic Pathways to Maintain Glioma Stem Cell Activity

Abstract

Chaperone-mediated autophagy (CMA) is a homeostatic process essential for the lysosomal degradation of a selected subset of the proteome. CMA activity directly depends on the levels of LAMP2A, a critical receptor for CMA substrate proteins at the lysosomal membrane. In glioblastoma (GBM), the most common and aggressive brain cancer in adulthood, high levels of LAMP2A in the tumor and tumor-associated pericytes have been linked to temozolomide resistance and tumor progression. However, the role of LAMP2A, and hence CMA, in any cancer stem cell type or in glioblastoma stem cells (GSC) remains unknown. In this work, we show that LAMP2A expression is enriched in patient-derived GSCs, and its depletion diminishes GSC-mediated tumorigenic activities.Conversely, overexpression of LAMP2A facilitates the acquisition of GSC properties. Proteomic and transcriptomic analysis of LAMP2A-depleted GSCs revealed reduced extracellular matrix (ECM) interaction effectors in both analyses. Moreover, pathways related to mitochondrial metabolism and the immune system were differentially deregulated at the proteome level. Furthermore, clinical samples of GBM tissue presented with overexpression of LAMP2, which correlated with advanced glioma grade and poor overall survival. In conclusion, these results identify a novel role of CMA in directly regulating GSCs activity via multiple pathways at the proteome and transcriptome levels. SIGNIFICANCEA receptor of chaperone-mediated autophagy regulates glioblastoma stem cells and may serve as a potential biomarker for advanced tumor grade and poor survival in this disease.Research.

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

“…Tumor cell infiltration and invasion of the brain parenchyma, which provides a proliferative environment, can occur via interaction between tumor cells and parenchyma cells such as PCs [ 17 ], creating a large network of microtubes and nanotubes that favors tumor development [ 16 , 55 ]. In addition, different cancer stem cells (CSCs) are also found in the TME, making GB difficult to treat [ 38 , 56 , 57 , 58 ]. Thus, the study of the TME, including the perivascular area with peritumoral PCs, is essential to make a good diagnosis of tumor progression.…”

“…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 ].…”

A selective type of autophagy to maintain glioma stem cell activity

“…Additionally, the proteomics analysis highlights an IFN signaling enhancement, as well as a decreased of MHC class II antigen-presentation-what together with proinflammatory cytokines, suggest the implication of this selective autophagy pathway in the immune effect in GBM mediated by the STAT components (10). The specific critical cytokines and factors are still pending of further validation; as it is also pending to check if the effect is specific of GSCs.…”

“…The modulation occurs in relation to different regulatory components-also to functional protein groups already described as substrates for this pathway. Those include: extra cellular matrix effectors, pathways related CMA mitochondrial metabolism and the immune system, and p53 or PI3K-AKT pathways (10). Energy homeostasis of the cells was reported during the last few years as intimately linked with the activity of CMA (3,4).…”

“…Interestingly, Auzmendi-Iriarte et al ( 10 ) showed a constitutional activity for CMA in the maintenance of GSC by regulating a variety of processes and pathways ( Figure 1 ). In addition to validate and extend the results in which LAMP2A increased were detected, higher amounts of LAMP2 have been linked to deficient overall survival in different (wide and global) GBM cohorts managed by the authors.…”