LIN28B promotes neuroblastoma metastasis and regulates PDZ binding kinase

• Main Authors: Dongdong Chen, Julie Cox, Jayabhargav Annam, Melanie Weingart, Grace Essien, Komal S. Rathi, Jo Lynne Rokita, Priya Khurana, Selma M. Cuya, Kristopher R. Bosse, Adeiye Pilgrim, Daisy Li, Cara Shields, Oskar Laur, John M. Maris, Robert W. Schnepp
• Format: Article
• Language: English
• Published: Elsevier 2020-06-01
• Series: Neoplasia: An International Journal for Oncology Research
• Subjects: Neuroblastoma; LIN28B; Let-7; PDZ binding kinase; Metastasis
• Online Access: http://www.sciencedirect.com/science/article/pii/S1476558620301135

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 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 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.