RT Journal Article
SR Electronic
T1 Spatial heterogeneity of cell-matrix adhesive forces predicts human glioblastoma migration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.06.080804
DO 10.1101/2020.05.06.080804
A1 Rasha Rezk
A1 Bill Zong Jia
A1 Astrid Wendler
A1 Ivan Dimov
A1 Colin Watts
A1 Athina E Markaki
A1 Kristian Franze
A1 Alexandre J Kabla
YR 2020
UL http://biorxiv.org/content/early/2020/05/08/2020.05.06.080804.abstract
AB Background Glioblastoma (GBM) is a highly aggressive incurable brain tumor. The main cause of mortality in GBM patients is the invasive rim of cells migrating away from the main tumor mass and invading healthy parts of the brain. Although motion is driven by forces, our current understanding of the physical factors involved in glioma infiltration remains limited. This study aims to investigate the adhesion properties within and between patients’ tumors on a cellular level and test whether these properties correlate with cell migration.Methods Nine tissue samples were taken from spatially separated sections during 5-aminolevulinic acid (5-ALA) fluorescence guided surgery. Navigated biopsy samples were collected from strongly fluorescent tumor cores, a weak fluorescent tumor rim, and non-fluorescent tumor margins. A microfluidics device was built to induce controlled shear forces to detach cells from monolayer cultures. Cells were cultured on low modulus polydimethylsiloxane representative of the stiffness of brain tissue. Cell migration and morphology were then obtained using time lapse microscopy.Results GBM cell populations from different tumor fractions of the same patient exhibited different migratory and adhesive behaviors. These differences were associated with sampling location and amount of 5-ALA fluorescence. Cells derived from weak- and non-fluorescent tumor tissue were smaller, adhered less well, and migrated quicker than cells derived from strongly fluorescent tumor mass.Conclusion GBM tumors are biomechanically heterogeneous. Selecting multiple populations and broad location sampling are therefore important to consider for drug testing.Key points GBM tumors are biomechanically heterogeneousGBM cell migration is inversely correlated with cell-matrix adhesion strength5-ALA fluorescence intensity during surgery correlates with the motility properties of GBM cellsImportance of the study This is the first study to compare single cell migration and cell-matrix adhesion strength of GBM, using cell lines derived from different tumors and from different regions within the same tumor. Not accounting for internal sampling location within each tumor obscures differences in cell morphology, motility and adhesion properties between patients. Peripherical and marginal tumor cells have different adhesion profiles and are highly migratory compared to those found in the core of the tumor. Aggressive regions of the tumor (highly motile) are linked to the spatial distribution of adhesion strength and are strongly associated with 5-ALA fluorescence intensity. Preclinical tests aimed at developing a treatment for GBM using anti-invasive drugs or adhesion inhibitors, would benefit from using cell lines derived from the tumor periphery (with low 5-ALA intensity) rather than cell lines derived from the tumor core.Competing Interest StatementThe authors have declared no competing interest.