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

Jaione Auzmendi-Iriarte, Maddalen Otaegi-Ugartemendia, Estefania Carrasco-Garcia, Mikel Azkargorta, Antonio Diaz, Ander Saenz-Antoñanzas, Joaquin Andrés Andermatten, Mikel Garcia-Puga, Idoia Garcia, Alejandro Elua-Pinin, Irune Ruiz, Nicolas Sampron, Felix Elortza, Ana Maria Cuervo, Ander Matheu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)1283-1297
Number of pages15
JournalCancer research
Volume82
Issue number7
DOIs
StatePublished - Apr 1 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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