Crosstalk between SHH and FGFR Signaling Pathways Controls Tissue Invasion in Medulloblastoma

Abstract

In the Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB), tumor initiation and progression are in part driven by smoothened (SMO) and fibroblast growth factor (FGF)-receptor (FGFR) signaling, respectively. We investigated the impact of the SMO-FGFR crosstalk on tumor growth and invasiveness in MB. We found that FGFR signaling represses GLI1 expression downstream of activated SMO in the SHH MB line DAOY and induces MKI67, HES1, and BMI1 in DAOY and in the group 3 MB line HD-MBO3. FGFR repression of GLI1 does not affect proliferation or viability, whereas inhibition of FGFR is necessary to release SMO-driven invasiveness. Conversely, SMO activation represses FGFR-driven sustained activation of nuclear ERK. Parallel activation of FGFR and SMO in ex vivo tumor cell-cerebellum slice co-cultures reduced invasion of tumor cells without affecting proliferation. In contrast, treatment of the cells with the SMO antagonist Sonidegib (LDE225) blocked invasion and proliferation in cerebellar slices. Thus, sustained, low-level SMO activation is necessary for proliferation and tissue invasion, whereas acute, pronounced activation of SMO can repress FGFR-driven invasiveness. This suggests that the tumor cell response is dependent on the relative local abundance of the two factors and indicates a paradigm of microenvironmental control of invasion in SHH MB through mutual control of SHH and FGFR signaling.

Real-time sensing of MAPK signaling in medulloblastoma cells reveals cellular evasion mechanism counteracting dasatinib blockade of ERK activation during invasion

“…One possibility is an altered de-repression of the ERK1/2 inhibitor DUSP4 by the polycomb group protein B lymphoma Mo-MLV insertion region 1 homolog (BMI), which promotes increased ERK1/2 activation and proliferation signaling in Gr4 MB [10] . BMI1 expression is up-regulated by bFGF-FGFR signaling in DAOY and the Gr3 MB line HD-MB03 [39] , which may explain incomplete dasatinib repression of nuclear ERK1/2 activity through a BMI1-DUSP4-dependent mechanism.…”

Construction and Validation of a 13-Gene Signature for Prognosis Prediction in Medulloblastoma

“…Additionally, these modules were interconnected via several hub genes, namely, FGFR1, BMP4, PAX6, PAX3, SOX9, and GLI2, all of which have been related to medulloblastomas in previous studies. Fibroblast growth factor receptor (FGFR) signaling is known to drive SHH medulloblastomas and is critical in regulating medulloblastoma invasion, and FGFR1 has been demonstrated to mediate inhibition of SHH medulloblastoma growth (Kumar et al, 2018;Neve et al, 2019). Bone morphogenetic proteins (BMPs) are known to regulate SHH-induced granule cell progenitor proliferation during cerebellar development and cell migration and invasion in Group 4 medulloblastoma model (Merve et al, 2014).…”

Isoform-specific aPKC renders primary cilia dispensable for Hedgehog signaling and basal cell carcinoma growth

“…ALMS1 has been identified through AP-MS studies as a possible binding partner of GPRASP2, a GPCR-associated sorting protein that has been implicated in SMO ciliary translocation (Jung et al, 2016). PCDH15 localization to kinocilia is dependent on FGFR1 activity (Honda et al, 2018), an interesting connection given that FGFR regulates GLI1 expression downstream of SMO in medulloblastomas (Neve et al, 2019). In addition, USH2A and PCDH15 can both bind directly to GBX2 (Roelseler et al, 2012), a HHresponsive protein in thalamic differentiation (Szabó et al, 2009).…”