Mechanical Compression Regulates Brain Cancer Cell Migration Through MEK1/Erk1 Pathway Activation and GDF15 Expression

Abstract

Mechanical compression is a common abnormality of brain tumors that has been shown to be responsible for the severe neurological defects of brain cancer patients representing a negative prognostic factor. Indeed, it is of note that patients that undergo resection exhibited higher survival rates than those subjected to biopsy only, suggesting that compressive forces generated during brain tumor growth play a key role in tumor progression. Despite the importance of mechanical compression in brain tumors, there is a lack of studies examining its direct effects on brain cancer cells and the mechanisms involved. In the present study, we used two brain cancer cell lines with distinct metastatic potential, the less aggressive H4 and the highly aggressive A172 cell lines, in order to study the effect of compression on their proliferative and migratory ability. Specifically, we used multicellular tumor spheroids (MCS) embedded in agarose matrix to show that compression strongly impaired their growth. Using mathematical modeling, we estimated the levels of compressive stress generated during the growth of brain MCS and then we applied the respective stress levels on brain cancer cell monolayers using our previously established transmembrane pressure device. By performing a scratch assay, we found that compression strongly induced the migration of the less aggressive H4 cells, while a less pronounced effect was observed for A172 cells. Analysis of the gene expression profile of both cell lines revealed that GDF15 and small GTPases are strongly regulated by mechanical compression, while GDF15 was further shown to be necessary for cells to migrate under compression. Through a phospho-proteomic screening, we further found that compressive stimulus is transmitted through the MEK1/Erk1 signaling pathway, which is also necessary for the migration of brain cancer cells. Finally, our results gave the first indication that GDF15 could regulate and being regulated by MEK1/Erk1 signaling pathway in order to facilitate the compression-induced brain cancer cell migration, rendering them along with small GTPases as potential targets for future anti-metastatic therapeutic innovations to treat brain tumors.

Keywords: Akt; GBM; c-Jun; metastasis; midline shift; phosphoproteomic screen; small GTPases.