TY - JOUR
T1 - Chaperone-Mediated Autophagy Controls Proteomic and Transcriptomic Pathways to Maintain Glioma Stem Cell Activity
AU - Auzmendi-Iriarte, Jaione
AU - Otaegi-Ugartemendia, Maddalen
AU - Carrasco-Garcia, Estefania
AU - Azkargorta, Mikel
AU - Diaz, Antonio
AU - Saenz-Antoñanzas, Ander
AU - Andermatten, Joaquin Andrés
AU - Garcia-Puga, Mikel
AU - Garcia, Idoia
AU - Elua-Pinin, Alejandro
AU - Ruiz, Irune
AU - Sampron, Nicolas
AU - Elortza, Felix
AU - Cuervo, Ana Maria
AU - Matheu, Ander
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2022/4/1
Y1 - 2022/4/1
N2 - 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 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 overexpression of LAMP2, which correlated with advanced glioma grade and poor overall survival. In conclusion, we identified a novel role of CMA in directly regulating GSCs activity via multiple pathways at the proteome and transcriptome levels. Significance: A receptor of chaperone-mediated autophagy regulates glioblastoma stem cells and may serve as a potential bio-marker for advanced tumor grade and poor survival in this disease.
AB - 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 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 overexpression of LAMP2, which correlated with advanced glioma grade and poor overall survival. In conclusion, we identified a novel role of CMA in directly regulating GSCs activity via multiple pathways at the proteome and transcriptome levels. Significance: A receptor of chaperone-mediated autophagy regulates glioblastoma stem cells and may serve as a potential bio-marker for advanced tumor grade and poor survival in this disease.
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U2 - 10.1158/0008-5472.CAN-21-2161
DO - 10.1158/0008-5472.CAN-21-2161
M3 - Article
C2 - 35131870
AN - SCOPUS:85128673731
SN - 0008-5472
VL - 82
SP - 1283
EP - 1297
JO - Cancer research
JF - Cancer research
IS - 7
ER -