期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 23, 期 12, 页码 -出版社
MDPI
DOI: 10.3390/ijms23126520
关键词
glioblastoma; extracellular matrix stiffening; tumor microenvironment; mechanical stress; PERK; unfolded protein response
资金
- China Scholarship Council [201908320416]
- University of Groningen
- Zernike Institute for Advanced Materials at the University of Groningen
- Bonus Incentive Scheme (Dutch Ministry for Education, Culture and Science (OCW))
Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults, and ECM stiffening plays a significant role in its progression. This study identifies a novel mechano-adaptive mechanism involving PERK/FLNA/F-Actin and provides new insights into the cellular adaptation to ECM stiffening.
Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults. In addition to genetic causes, the tumor microenvironment (TME), including stiffening of the extracellular matrix (ECM), is a main driver of GBM progression. Mechano-transduction and the unfolded protein response (UPR) are essential for tumor-cell adaptation to harsh TME conditions. Here, we studied the effect of a variable stiff ECM on the morphology and malignant properties of GBM stem cells (GSCs) and, moreover, examined the possible involvement of the UPR sensor PERK herein. For this, stiffness-tunable human blood plasma (HBP)/alginate hydrogels were generated to mimic ECM stiffening. GSCs showed stiffness-dependent adaptation characterized by elongated morphology, increased proliferation, and motility which was accompanied by F-Actin cytoskeletal remodeling. Interestingly, in PERK-deficient GSCs, stiffness adaptation was severely impaired, which was evidenced by low F-Actin levels, the absence of F-Actin remodeling, and decreased cell proliferation and migration. This impairment could be linked with Filamin-A (FLN-A) expression, a known interactor of PERK, which was strongly reduced in PERK-deficient GSCs. In conclusion, we identified a novel PERK/FLNA/F-Actin mechano-adaptive mechanism and found a new function for PERK in the cellular adaptation to ECM stiffening.
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