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 ...