Abstract The metastatic potential of tumors depends in part on their response to growth factors available in the tumor microenvironment. We addressed how micro-environmental 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 pharmacological blockade of FGFR represses brain tissue infiltration in vivo. TGF-ß regulates pro-migratory bFGF function in a context-dependent manner. Under low bFGF, the non-canonical TGF-ß 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-ß counters inactivation of FRS2 and restores pro-invasive signaling 1. These findings pinpoint coincidence detection of bFGF and TGF-ß signaling by FRS2 as a mechanism that controls tumor cell invasion and identified targeting of FRS2 as a rational strategy to abrogate aberrant FGFR signaling independent of kinase inhibition. Using computer-assisted compound discovery, we screened chemical libraries for potential small molecule inhibitors of the interaction between FGFR and FRS2. Using functional testing, we selected potential hits that block invasion comparable to current small molecule FGFR kinase inhibitors and that bind FRS2 in the relevant domain. Thus, our study provides first evidence of rationally discovered, precisely acting small molecule interaction inhibitors with the potential to effectively target pro-invasive signaling in MB and other FGFR-driven cancers. 1. Santhana Kumar K et al. Cell Rep. 2018; 23: 3798–812