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.
Highlights
The crosstalk between signaling pathways in eukaryotic cells controls cellular functions involved in proliferation, differentiation, viability, and motile behavior
BFGF pre-treatment of Sonic Hedgehog (SHH) MB tumor cells derived from a Ptch+/− mouse or direct injection of high concentrations of be dependent on FGF2 (bFGF) into Ptch+/− MB tumors that were orthotopically implanted in recipient mice prevented tumor growth or caused regression, respectively [5]
We found that SAG treatment caused a significant increase in GLI1 expression in DAOY cells without affecting the expression of the other genes. bFGF repressed SAG-induced GLI1 and caused significant increases in HES1, MKI67, and BMI1 in both cell lines (Figure 3D,E)
Summary
The crosstalk between signaling pathways in eukaryotic cells controls cellular functions involved in proliferation, differentiation, viability, and motile behavior. BFGF pre-treatment of SHH MB tumor cells derived from a Ptch+/− mouse or direct injection of high concentrations of bFGF into Ptch+/− MB tumors that were orthotopically implanted in recipient mice prevented tumor growth or caused regression, respectively [5] This raises the question of a dichotomous pro-invasive/anti-proliferative function of bFGF in MB tumors with activated SHH signaling that may impact on the growth and the dissemination of the tumor cells. Hedgehog (Hh) signaling is an evolutionary conserved signaling pathway It regulates a multitude of cellular processes during development, embryonic patterning, organ morphogenesis, and growth control by regulating cell proliferation, differentiation, and migration [6]. We test whether combined activation of FGFR and SMO affects proliferation and invasiveness in MB cells
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