Abstract A025: The role of matrix metalloproteinase-9 in neuropeptide Y-mediated osteolysis in Ewing sarcoma

Abstract

Ewing sarcoma (ES) is an aggressive pediatric cancer that affects bone and soft tissues. The mechanism of ES bone metastasis is poorly understood. Previous data from our group implicates neuropeptide Y (NPY) and its Y5 receptor (Y5R) in bone metastasis and invasion. We determined that in ES cells, the NPY/Y5R axis promotes the activity of matrix metalloproteinase-9 (MMP-9), which degrades collagen I, a key component of the extracellular bone matrix. MMP-9 expression and activity are reduced in cells with NPY/Y5R knockdown (KD). Furthermore, MMP-9 expression is increased in cells grown in a stiff collagen matrix, which upregulates NPY and Y5R expression. In ES xenografts, MMP-9 immunoreactivity is elevated at the tumor-bone border, but this phenomenon is not observed in tissues from xenografts with NPY KD or treated with a Y5R antagonist. These results demonstrate that MMP-9 expression is driven by the NPY/Y5R pathway. To examine the role of MMP-9 in NPY/Y5R-mediated osteolysis, we used Sirius red staining to visualize collagen fibers and found that collagen degradation by ES cells was impaired in cells with NPY/Y5R KD. Establishing the regulation and role of MMP-9 in NPY/Y5R-directed osteolysis highlights this pathway as a potential therapeutic target to reduce ES bone metastasis.