PT  - JOURNAL ARTICLE
AU  - Odessa R. Yabut
AU  - Hector Gomez
AU  - Jessica Arela
AU  - Jesse Garcia Castillo
AU  - Thomas Ngo
AU  - Samuel J. Pleasure
TI  - Aberrant FGF signaling promotes granule neuron precursor expansion in SHH subgroup infantile medulloblastoma
AID  - 10.1101/2021.06.23.449636
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.06.23.449636
4099  - http://biorxiv.org/content/early/2021/06/24/2021.06.23.449636.short
4100  - http://biorxiv.org/content/early/2021/06/24/2021.06.23.449636.full
AB  - Mutations in Sonic Hedgehog (SHH) signaling pathway genes, e.g. Suppressor of Fused (SUFU), drive granule neuron precursors (GNP) to form medulloblastomas (MBSHH). However, how different molecular lesions in the Shh pathway drive transformation is frequently unclear, and in particular, SUFU mutations in the cerebellum seem distinct. In this study, we show that fibroblast growth factor 5 (FGF5) signaling is integral for many infantile MBSHH cases. We found that FGF5 expression is uniquely upregulated in infantile MBSHH tumors. Also, in mice carrying loss-of-function SUFU mutations (Sufu-cKO), FGF5 is ectopically expressed specifically along the secondary fissure where GNPs harboring preneoplastic DNA lesions are massively expanded and FGFR signaling is also ectopically activated in this region. Treatment with an FGFR antagonist rescues the severe GNP hyperplasia and restores cerebellar architecture. Thus, direct inhibition of FGF signaling may be a promising and novel therapeutic candidate for infantile MBSHH.Competing Interest StatementThe authors have declared no competing interest.