These authors found a significant association of disorganized collagen filaments in GBM with a poorer patient survival. Primary GBM and human GBM xenografted mice showed increased levels of collagen in tumors from tissue microarrays using second-harmonic generation microscopy. Collagen is not an ECM component in normal brain but is found in the basement membrane of blood vessels. Although laminin is not a component of axons, it is embedded in an ECM enriched with laminin. Especially in the brain, higher amounts of laminin and hyaluronic acid are found, where they contribute to normal brain function and tumor stiffness regulating tumor cell motility. Specific tissue types harbor different ratios of ECM components, such as collagen, laminin, fibronectin and hyaluronic acid.
Cell-cell as well as cell-ECM interactions are crucial for a cell to instantly respond to the environment and further propagate the signals that control cell shape and motility. Depending upon the cell type, two main migratory phenotypes can be differentiated: (1) single cells, which are amoeboid or mesenchymal, and (2) multicellular, or so-called collective cell migration. For the ability of cells to migrate, dynamic and spatially regulated changes of the cytoskeleton, cell adhesion and cell interactions with the extracellular matrix (ECM) must occur. 3D microfibers represent an important tool to model brain metastasizing tumor cells, where RHO-inhibitors could play an essential role for improved therapy.Ĭell migration and invasion are hallmarks of development and cancer. GBM and TNBC cells with PTEN loss of function have an affinity for stiff brain structures promoting metastasis. Conclusions: This study demonstrates a significant role of the PTEN genotype and RHOB expression for durotaxis, adhesion and migration dependent on 3D. Functional studies concerning RHOB-ROCK-PTEN signaling confirmed the essential role for the above cellular processes. Results: In contrast to the PTEN wildtype, GBM and TNBC cells with PTEN loss of function yielded enhanced durotaxis, topotaxis, adhesion, amoeboid migration on 3D microfibers and significant high RHOB expression. RNA-sequencing and qPCR of tumor cells in 3D with microfibers were performed, while scanning electron microscopy and confocal microscopy addressed cell morphology. GBM and TNBC cell lines with opposing PTEN genotypes were analyzed with RHO-ROCK-PTEN inhibitors and PTEN rescue using live-cell imaging. Methods: 3D microfibers and scaffolds were printed using melt electrowriting. To understand signaling, controlling the dynamics and mechanics of brain tumor cell migration, we implemented GBM and TNBC cell lines and designed 3D aligned microfibers and scaffolds mimicking brain structures. Regarding GBM and brain metastasizing TNBC, we conclude that RHOB inhibitors could play a novel role for improved therapy response and patient outcome.īackground: Glioblastoma multiforme (GBM) and metastatic triple-negative breast cancer (TNBC) with PTEN mutations often lead to brain dissemination with poor patient outcome, thus new therapeutic targets are needed. Depending on the PTEN genotype, RHO-ROCK-PTEN inhibitors or PTEN rescue significantly regulated these properties. GBM and TNBC cell lines with PTEN loss of function and high RHOB expression exhibited amoeboid morphology with increased durotaxis, binding and migration speed on 3D microfibers, in contrast to the PTEN wildtype. Using 3D aligned printed microfibers mimicking brain structures proved that RHOB, in addition to ROCK and PTEN signaling, were essential for GBM and TNBC 3D cell migration. There is a need for new therapeutic targets to blunt brain tumor spreading. GBM, and possibly TNBC, migrate on axons and blood vessels to disseminate in the brain however, the mechanism is unresolved. Glioblastoma multiforme (GBM) and metastatic triple-negative breast cancer (TNBC) with PTEN mutations are associated with brain tumor spreading and poor patient outcomes.
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