TGF-β Determines the Pro-migratory Potential of bFGF Signaling in Medulloblastoma

Abstract

Summary: The microenvironment shapes cell behavior and determines metastatic outcomes of tumors. We addressed how microenvironmental cues control tumor cell invasion in pediatric medulloblastoma (MB). We show that bFGF promotes MB tumor cell invasion through FGF receptor (FGFR) in vitro and that blockade of FGFR represses brain tissue infiltration in vivo. TGF-β regulates pro-migratory bFGF function in a context-dependent manner. Under low bFGF, the non-canonical TGF-β pathway causes ROCK activation and cortical translocation of ERK1/2, which antagonizes FGFR signaling by inactivating FGFR substrate 2 (FRS2), and promotes a contractile, non-motile phenotype. Under high bFGF, negative-feedback regulation of FRS2 by bFGF-induced ERK1/2 causes repression of the FGFR pathway. Under these conditions, TGF-β counters inactivation of FRS2 and restores pro-migratory signaling. These findings pinpoint coincidence detection of bFGF and TGF-β signaling by FRS2 as a mechanism that controls tumor cell invasion. Thus, targeting FRS2 represents an emerging strategy to abrogate aberrant FGFR signaling. : Santhana Kumar et al. describe how growth factors in the microenvironment of medulloblastoma, the most common malignant brain tumor in children, are sensed by the tumor cells and how they respond to these factors. They identify the adaptor protein FRS2 as a key molecule controlling growth factor-induced tissue infiltration. Keywords: medulloblastoma, migration, invasion, FGFR1 signaling, FRS2, bFGF, TGF-β signaling, tumor microenvironment, organotypic cerebellum slice culture