Substrate stiffness effect on molecular crosstalk of epithelial-mesenchymal transition mediators of human glioblastoma cells

Abstract

The complexity of the microenvironment effects on cell response, show accumulating evidence that glioblastoma (GBM) migration and invasiveness are influenced by the mechanical rigidity of their surroundings. The epithelial–mesenchymal transition (EMT) is a well-recognized driving force of the invasive behavior of cancer. However, the primary mechanisms of EMT initiation and progression remain unclear. We have previously showed that certain substrate stiffness can selectively stimulate human GBM U251-MG and GL15 glioblastoma cell lines motility. The present study unifies several known EMT mediators to uncover the reason of the regulation and response to these stiffnesses. Our results revealed that changing the rigidity of the mechanical environment tuned the response of both cell lines through change in morphological features, epithelial-mesenchymal markers (E-, N-Cadherin), EGFR and ROS expressions in an interrelated manner. Specifically, a stiffer microenvironment induced a mesenchymal cell shape, a more fragmented morphology, higher intracellular cytosolic ROS expression and lower mitochondrial ROS. Finally, we observed that cells more motile showed a more depolarized mitochondrial membrane potential. Unravelling the process that regulates GBM cells’ infiltrative behavior could provide new opportunities for identification of new targets and less invasive approaches for treatment.

Magnetically Stimulated Integrin Binding Alters Cell Polarity and Affects Epithelial–Mesenchymal Plasticity in Metastatic Cancer Cells

“…The noticeable feature of EMT is the reorganization of the actin cytoskeleton, and some studies have elucidated the regulatory mechanisms regulating this process . The stiffness of the extracellular matrix (ECM) substrates promotes the proliferation of cancer cells …”

“…28 The stiffness of the extracellular matrix (ECM) substrates promotes the proliferation of cancer cells. 29 ECM rigidity affects cellular processes through intracellular signaling pathways through mechanotransduction and alters the phenotype of the cells, further inducing rapid EMT and metastasis in tumors. 30 Besides, actin stress fibers were more prominent in cells grown on rigid than soft substrates.…”

Influence of C60 Nanofilm on the Expression of Selected Markers of Mesenchymal–Epithelial Transition in Hepatocellular Carcinoma

“…Many factors have been reported to regulate EMT, including growth factors [9], transcription factors [21] and surface stiffness [22]. In this work, we evaluated for the first time whether cell growth on the surface of fullerene C 60 promotes MET and whether there is a negative correlation between the epithelial phenotype of cells and the growth factor cocktail-induced oxidative stress, inflammation and autophagy.…”