Neuroblastoma is the most common extracranial solid tumor in children. Whilst advances in treatment have increased the survival rate of low-risk neuroblastoma patients, the survival rate remains poor for high-risk neuroblastoma patients. In this study, immunohistochemistry and RNA-Seq analysis of neuroblastoma patient samples revealed that high expression of p120ctn positively correlated with metastasis and poor outcome. Knockdown of p120ctn activated the Wnt signaling pathway and reduced the expression of the transcription factor N-Myc. Contrary to the function of p120ctn as a tumor suppressor, depletion of p120ctn induced mesenchymal-to-epithelial transition, attenuated proliferation, migration, invasion and sensitized the neuroblastoma cells to doxorubicin. Coimmunoprecipitation and phosphoproteomics revealed that p120ctn differentially regulates RhoA activation and Twist phosphorylation in a cell type-dependent manner. Induction of epithelial lineage by overexpressing E-cadherin reduced the expression of p120ctn and sensitised the neuroblastoma cells to doxorubicin. Overall, this study highlights cell lineage alteration as an alternative to treat high-risk neuroblastoma patients.
Fonseka et al. JCI, In revision