Calmodulin-kinases regulate basal and estrogen stimulated medulloblastoma migration via Rac1

Medulloblastoma is a highly prevalent pediatric central nervous system malignancy originating in the cerebellum, with a strong propensity for metastatic migration to the leptomeninges, which greatly increases mortality. While numerous investigations are focused on the molecular mechanisms of medulloblastoma histogenesis, the signaling pathways regulating migration are still poorly understood. Medulloblastoma likely arises from aberrant proliferative signaling in cerebellar granule precursor cells during development, and estrogen is a morphogen that promotes medulloblastoma cell migration. It has been previously shown that the calcium/calmodulin activated kinase kinase (CaMKK) pathway promotes cerebellar granule precursor migration and differentiation during normal cerebellar development via CaMKIV. Here we investigate the regulatory role of the CaMKK pathway in migration of the human medulloblastoma DAOY and cerebellar granule cells. Using pharmacological inhibitors and dominant negative approaches, we demonstrate that the CaMKK/CaMKI cascade regulates basal medulloblastoma cell migration via Rac1, in part by activation of the RacGEF, βPIX. Additionally, pharmacological inhibition of CaMKK blocks both the estrogen induced Rac1 activation and medulloblastoma migration. The CaMKK signaling module described here is one of the first reported calcium regulated pathways that modulates medulloblastoma migration. Since tumor dissemination requires cell migration to ectopic sites, this CaMKK pathway may be a putative therapeutic target to limit medulloblastoma metastasis.