PMID- 35131870 OWN - NLM STAT- MEDLINE DCOM- 20220405 LR - 20230206 IS - 1538-7445 (Electronic) IS - 0008-5472 (Print) IS - 0008-5472 (Linking) VI - 82 IP - 7 DP - 2022 Apr 1 TI - Chaperone-Mediated Autophagy Controls Proteomic and Transcriptomic Pathways to Maintain Glioma Stem Cell Activity. PG - 1283-1297 LID - 10.1158/0008-5472.CAN-21-2161 [doi] 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 biomarker for advanced tumor grade and poor survival in this disease. CI - (c)2022 The Authors; Published by the American Association for Cancer Research. FAU - Auzmendi-Iriarte, Jaione AU - Auzmendi-Iriarte J AD - Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain. FAU - Otaegi-Ugartemendia, Maddalen AU - Otaegi-Ugartemendia M AD - Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain. FAU - Carrasco-Garcia, Estefania AU - Carrasco-Garcia E AD - Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain. FAU - Azkargorta, Mikel AU - Azkargorta M AD - Proteomics Platform, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), CIBERehd, ProteoRed-ISCIII, Spain. FAU - Diaz, Antonio AU - Diaz A AD - Department of Development and Molecular Biology, Albert Einstein College of Medicine, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York. FAU - Saenz-Antonanzas, Ander AU - Saenz-Antonanzas A AD - Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain. FAU - Andermatten, Joaquin Andres AU - Andermatten JA AUID- ORCID: 0000-0002-6402-519X AD - Donostia University Hospital, Osakidetza, San Sebastian, Spain. FAU - Garcia-Puga, Mikel AU - Garcia-Puga M AUID- ORCID: 0000-0002-2975-934X AD - Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain. FAU - Garcia, Idoia AU - Garcia I AD - Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain. FAU - Elua-Pinin, Alejandro AU - Elua-Pinin A AD - Donostia University Hospital, Osakidetza, San Sebastian, Spain. FAU - Ruiz, Irune AU - Ruiz I AD - Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain. AD - Donostia University Hospital, Osakidetza, San Sebastian, Spain. FAU - Sampron, Nicolas AU - Sampron N AD - Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain. AD - Donostia University Hospital, Osakidetza, San Sebastian, Spain. FAU - Elortza, Felix AU - Elortza F AUID- ORCID: 0000-0001-8839-5438 AD - Proteomics Platform, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), CIBERehd, ProteoRed-ISCIII, Spain. FAU - Cuervo, Ana Maria AU - Cuervo AM AD - Department of Development and Molecular Biology, Albert Einstein College of Medicine, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York. FAU - Matheu, Ander AU - Matheu A AD - Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain. AD - CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), Madrid, Spain. AD - IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. LA - eng GR - P30 AG038072/AG/NIA NIH HHS/United States GR - R37 AG021904/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (Lysosomal-Associated Membrane Protein 2) SB - IM CIN - Stem Cell Investig. 2023 Jan 06;10:1. PMID: 36742282 MH - Adult MH - Autophagy MH - *Chaperone-Mediated Autophagy/genetics MH - *Glioma/genetics MH - Humans MH - Lysosomal-Associated Membrane Protein 2/genetics/metabolism MH - Neoplastic Stem Cells/metabolism MH - Proteomics MH - Transcriptome PMC - PMC9359743 EDAT- 2022/02/09 06:00 MHDA- 2022/04/06 06:00 PMCR- 2022/08/08 CRDT- 2022/02/08 05:48 PHST- 2021/07/05 00:00 [received] PHST- 2021/12/15 00:00 [revised] PHST- 2022/01/27 00:00 [accepted] PHST- 2022/02/09 06:00 [pubmed] PHST- 2022/04/06 06:00 [medline] PHST- 2022/02/08 05:48 [entrez] PHST- 2022/08/08 00:00 [pmc-release] AID - 0008-5472.CAN-21-2161 [pii] AID - CAN-21-2161 [pii] AID - 10.1158/0008-5472.CAN-21-2161 [doi] PST - ppublish SO - Cancer Res. 2022 Apr 1;82(7):1283-1297. doi: 10.1158/0008-5472.CAN-21-2161.