REELIN/DISABLED-1-signaling in glioma cell migration and invasion

The proteins Reelin and Disabled-1 (DAB1) are known to be key regulators in embryonal development of the central nervous system by controlling neuronal migration. Latest research revealed that Reelin/DAB1 signaling exhibits tumor suppressive functions in several cancers (e.g. hepatocellular carcinoma, breast cancer, esophageal cancer or pancreatic cancer), but until now, effects of Reelin and DAB1 on brain tumors were mostly unknown. As previous work of our laboratory indicated frequent epigenetic inactivation of Reelin in high-grade gliomas, research was pursued by examining the motility of glioblastoma cells in response to Reelin/DAB1 signaling. In the present doctoral thesis, migration and invasion of U87 and U251 cells, overexpressing either the intracellular protein DAB1 or the corresponding inactive 5F mutant, was analyzed after Reelin stimulation. Both, U87 and U251 cells, showed significantly reduced migration on fibronectin and laminin under the influence of Reelin and DAB1. Further data suggests that effects of DAB1-independent Reelin signaling, as e.g. on integrins (α3β1 and α5β1 integrin, for example), might contribute considerably to the tumor suppressive functions of this pathway. Besides this, also Reelin-independent DAB1 effects induced by other upstream mediators might play a major role in regulating glioblastoma invasion. Further experiments comprised matrigel invasion assays as well as the investigation of the underlying downstream targets of Reelin and DAB1. Taken together, Reelin and DAB1 were identified as novel players in the regulation of glioblastoma cell migration suggesting tumor suppressive functions of Reelin/DAB1 signaling in high-grade gliomas