Targeting BMP9-promoted human osteosarcoma growth by inactivation of notch signaling

Area of Science:

• Oncology
• Molecular Biology
• Bone Cancer Research

Background:

• Osteosarcoma (OS) is the most common primary bone cancer, often with poor prognosis due to metastasis and chemoresistance.
• The molecular drivers of OS pathogenesis and growth remain incompletely understood.
• Previous studies indicated OS cells resist BMP9-induced osteogenesis but favor proliferation.

Purpose of the Study:

• To investigate the role of Notch signaling in mediating BMP9-promoted proliferation and tumor growth in human osteosarcoma.
• To determine if targeting Notch signaling could be a therapeutic strategy for OS.

Main Methods:

• Detected expression of Notch pathway components (Notch1-3, DLL1, JAG1-2) in OS cell lines.
• Utilized a dominant-negative Notch1 mutant (dnNotch1) and a γ-secretase inhibitor (Compound E) to block Notch signaling.
• Assessed effects on OS cell proliferation, migration, cell cycle progression, and tumor growth in vivo.

Main Results:

• Notch signaling components are expressed in most OS cell lines.
• BMP9-induced OS cell proliferation, migration, and S/G2 cell cycle progression were inhibited by dnNotch1 and Compound E.
• BMP9-promoted tumor growth and osteolytic lesions in vivo were significantly reduced by dnNotch1.
• BMP9 up-regulated Notch1, Notch3, DLL1, JAG1, and induced NICD nuclear accumulation, which was blocked by Compound E.

Conclusions:

• BMP9-promoted osteosarcoma proliferation and tumor growth are, in part, mediated by Notch signaling.
• Osteogenic BMPs may act as upstream regulators of Notch signaling in OS tumorigenesis.
• Pharmacologic inhibition of Notch signaling presents a potential therapeutic avenue for human osteosarcoma.