Although activating mutations of the anaplastic lymphoma kinase (ALK) membrane receptor occur in ∼10% of neuroblastoma (NB) tumors, the role of the wild-type (WT) receptor,
which is aberrantly expressed in most non-mutated cases, is unclear. Both WT and mutant proteins undergo ECD cleavage. In a recent study published in Cell, first author, Hao Huang, PhD, and senior author, Rani George, MD, PhD,
show that extracellular domain (ECD) cleavage of the ALK cell surface tyrosine kinase receptor mediates neuroblastoma cell migration through induction of an epithelial-to-mesenchymal transition (EMT) gene signature. They also show that ECD cleavage
is caused by matrix metalloproteinase 9 (MMP-9), whose inhibition leads to decreased NB cell migration. Proteolytic cleavage of the ECD of WT ALK, which is expressed in most NB cases, promotes metastasis. By targeting that process, these adverse cancer-associated
features of ALK cleavage can be circumvented, raising the possibility of MMP-9 inhibition, either singly or in combination with that of ALK in patients with NB ...