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
