PUBLICATION
The polarity protein Par3 coordinates positively self-renewal and negatively invasiveness in glioblastoma
- Authors
- Dadras, M.S., Caja, L., Mezheyeuski, A., Liu, S., Gélabert, C., Gomez-Puerto, M.C., Gallini, R., Rubin, C.J., Ten Dijke, P., Heldin, C.H., Moustakas, A.
- ID
- ZDB-PUB-220203-13
- Date
- 2021
- Source
- Cell Death & Disease 12: 932 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism*
- Adenosine Triphosphate/metabolism
- Animals
- Antioxidants/metabolism
- Cell Cycle Proteins/genetics
- Cell Cycle Proteins/metabolism*
- Cell Line, Tumor
- Cell Movement
- Cell Polarity*/genetics
- Cell Self Renewal*
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Gene Silencing
- Glioblastoma/genetics
- Glioblastoma/pathology*
- Humans
- Mitochondria/metabolism
- Neoplasm Invasiveness
- Oxidative Phosphorylation
- Reactive Oxygen Species/metabolism
- Spheroids, Cellular/metabolism
- Spheroids, Cellular/pathology
- Transcriptome/genetics
- Zebrafish
- PubMed
- 34642295 Full text @ Cell Death Dis.
Citation
Dadras, M.S., Caja, L., Mezheyeuski, A., Liu, S., Gélabert, C., Gomez-Puerto, M.C., Gallini, R., Rubin, C.J., Ten Dijke, P., Heldin, C.H., Moustakas, A. (2021) The polarity protein Par3 coordinates positively self-renewal and negatively invasiveness in glioblastoma. Cell Death & Disease. 12:932.
Abstract
Glioblastoma (GBM) is a brain malignancy characterized by invasiveness to the surrounding brain tissue and by stem-like cells, which propagate the tumor and may also regulate invasiveness. During brain development, polarity proteins, such as Par3, regulate asymmetric cell division of neuro-glial progenitors and neurite motility. We, therefore, studied the role of the Par3 protein (encoded by PARD3) in GBM. GBM patient transcriptomic data and patient-derived culture analysis indicated diverse levels of expression of PARD3 across and independent from subtypes. Multiplex immunolocalization in GBM tumors identified Par3 protein enrichment in SOX2-, CD133-, and NESTIN-positive (stem-like) cells. Analysis of GBM cultures of the three subtypes (proneural, classical, mesenchymal), revealed decreased gliomasphere forming capacity and enhanced invasiveness upon silencing Par3. GBM cultures with suppressed Par3 showed low expression of stemness (SOX2 and NESTIN) but higher expression of differentiation (GFAP) genes. Moreover, Par3 silencing reduced the expression of a set of genes encoding mitochondrial enzymes that generate ATP. Accordingly, silencing Par3 reduced ATP production and concomitantly increased reactive oxygen species. The latter was required for the enhanced migration observed upon silencing of Par3 as anti-oxidants blocked the enhanced migration. These findings support the notion that Par3 exerts homeostatic redox control, which could limit the tumor cell-derived pool of oxygen radicals, and thereby the tumorigenicity of GBM.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping