The Unfolded Protein Response Sensor PERK Mediates Stiffness-Dependent Adaptation in Glioblastoma Cells

Int J Mol Sci. 2022 Jun 10;23(12):6520. doi: 10.3390/ijms23126520.

Abstract

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.

Keywords: PERK; extracellular matrix stiffening; glioblastoma; mechanical stress; tumor microenvironment; unfolded protein response.

MeSH terms

  • Actins / metabolism
  • Adult
  • Brain Neoplasms* / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Glioblastoma* / metabolism
  • Humans
  • Tumor Microenvironment
  • Unfolded Protein Response

Substances

  • Actins

Grants and funding

D.L. was supported by the China Scholarship Council [201908320416] and the University of Groningen. M.K. (Mohammad Khoonkari) was financially supported by the Zernike Institute for Advanced Materials at the University of Groningen, including funding from the Bonus Incentive Scheme (of the Dutch Ministry for Education, Culture and Science (OCW)).