Extracellular domain shedding of the ALK receptor mediates neuroblastoma cell migration
Hao Huang,
Alexander Gont,
Lynn Kee,
Ruben Dries,
Kathrin Pfeifer,
Bandana Sharma,
David N. Debruyne,
Matthew Harlow,
Satyaki Sengupta,
Jikui Guan,
Caleb M. Yeung,
Wenchao Wang,
Bengt Hallberg,
Ruth H. Palmer,
Meredith S. Irwin,
Rani E. George
Affiliations
Hao Huang
Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Alexander Gont
Department of Pediatrics and Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
Lynn Kee
Department of Pediatrics and Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
Ruben Dries
Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Kathrin Pfeifer
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Bandana Sharma
Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
David N. Debruyne
Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Matthew Harlow
Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Satyaki Sengupta
Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Jikui Guan
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Caleb M. Yeung
Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Wenchao Wang
Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Bengt Hallberg
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Ruth H. Palmer
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Meredith S. Irwin
Department of Pediatrics and Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Corresponding author
Rani E. George
Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Corresponding author
Summary: 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 extracellular domain (ECD) cleavage. Here, we map the cleavage site to Asn654-Leu655 and demonstrate that cleavage inhibition of WT ALK significantly impedes NB cell migration with subsequent prolongation of survival in mouse models. Cleavage inhibition results in the downregulation of an epithelial-to-mesenchymal transition (EMT) gene signature, with decreased nuclear localization and occupancy of β-catenin at EMT gene promoters. We further show that cleavage is mediated by matrix metalloproteinase 9, whose genetic and pharmacologic inactivation inhibits cleavage and decreases NB cell migration. Together, our results indicate a pivotal role for WT ALK ECD cleavage in NB pathogenesis, which may be harnessed for therapeutic benefit.
