Despite multi-modality treatments, prognosis for advanced stage
neuroblastoma (NB) remains challenging with residual long-term disabilities in survivors. Advanced stage NB is metastatic, which is a principal cause of
cancer-related deaths. We presently document a primary role of MDA-9 in NB progression and define the molecular mechanisms by which MDA-9 promotes transformed phenotypes. NB cell lines and clinical samples display elevated MDA-9 expression and bioinformatic analysis supports an association between elevated MDA-9 and bone
metastasis and poor prognosis. Genetic (shmda-9, mda-9 siRNA) or pharmacological (small molecule inhibitor of
protein-
protein interactions; PDZ1i) blockade of MDA-9 decreases NB migration, invasion, and
metastasis. Blocking mda-9 expression or disrupting MDA-9 partner
protein interactions downregulates
integrin α6 and β4, diminishing Src activity and suppressing Rho-Rac-Cdc42 activity. These signaling changes inhibit
cofilin and
matrix metalloproteinases reducing in vitro and in vivo NB cell migration. Overexpression of
integrin α6 and β4 rescues the invasion phenotype and increases Src activity, supporting
integrins as essential regulators of MDA-9-mediated NB migration and invasion. We identify MDA-9 as a key contributor to NB pathogenesis and show that genetic or pharmacological inhibition suppresses NB pathogenesis by an
integrin-mediated Src-disruption pathway.