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

Area of Science:

• Neuro-oncology
• Molecular biology
• Cancer signaling pathways

Background:

• Sonic Hedgehog (SHH) medulloblastoma (MB) is driven by SMO and FGFR signaling.
• Understanding the crosstalk between SMO and FGFR is crucial for MB progression.

Purpose of the Study:

• To investigate the impact of SMO-FGFR signaling crosstalk on medulloblastoma growth and invasiveness.
• To elucidate the mechanisms by which SMO and FGFR signaling pathways interact.

Main Methods:

• Utilized SHH MB cell line (DAOY) and Group 3 MB cell line (HD-MBO3).
• Investigated gene expression changes (GLI1, MKI67, HES1, BMI1) and ERK activation.
• Employed ex vivo tumor cell-cerebellum slice co-cultures.
• Administered SMO antagonist Sonidegib (LDE225).

Main Results:

• FGFR signaling repressed GLI1 expression downstream of SMO activation in DAOY cells.
• FGFR signaling induced MKI67, HES1, and BMI1 in both DAOY and HD-MBO3 cells.
• FGFR inhibition released SMO-driven invasiveness, while SMO activation repressed FGFR-driven ERK signaling.
• Parallel SMO and FGFR activation reduced tumor cell invasion without affecting proliferation in co-cultures.
• Sonidegib treatment blocked both invasion and proliferation in cerebellar slices.

Conclusions:

• SMO and FGFR signaling pathways exhibit mutual control over medulloblastoma cell proliferation and invasion.
• Tumor cell response depends on the relative abundance of SMO and FGFR signaling.
• This crosstalk represents a paradigm for microenvironmental control of invasion in SHH medulloblastoma.