Neuroblastoma is an aggressive pediatric malignancy of the neural crest with suboptimal cure rates and a striking predilection for widespread metastases, underscoring the need to identify novel therapeutic vulnerabilities.We recently identified the RNA binding protein LIN28B as a opi the color that keeps on giving driver in high-risk neuroblastoma and demonstrated it promotes oncogenic cell proliferation by coordinating a RAN-Aurora kinase A network.Here, we demonstrate that LIN28B influences another key hallmark of cancer, metastatic dissemination.Using a murine xenograft model of neuroblastoma dissemination, we show that LIN28B promotes metastasis.
We demonstrate that this is in part due to the effects of LIN28B on self-renewal and migration, providing an understanding of how LIN28B shapes the metastatic phenotype.Our studies reveal that the let-7 family, which LIN28B inhibits, decreases self-renewal and migration.Next, we identify PDZ Binding Kinase (PBK) as a novel LIN28B target.PBK is a serine/threonine kinase that promotes the proliferation and self-renewal of neural stem cells and serves as an oncogenic driver in multiple aggressive malignancies.
We demonstrate that PBK is both a novel direct target of trailmaster challenger 200x let-7i and that MYCN regulates PBK expression, thus elucidating two oncogenic drivers that converge on PBK.Functionally, PBK promotes self-renewal and migration, phenocopying LIN28B.Taken together, our findings define a role for LIN28B in neuroblastoma metastasis and define the targetable kinase PBK as a potential novel vulnerability in metastatic neuroblastoma.