LIN28B promotes neuroblastoma metastasis and regulates PDZ binding kinase

• Type of Material: Article
• Authors: Dongdong Chen, Emory University; Julie Cox, Childrens Hospital of Philadelphia; Jayabhargav Annam, Emory University; Melanie Weingart, Childrens Hospital of Philadelphia; Grace Essien, Emory University; Komal S. Rathi, Childrens Hospital of Philadelphia; Jo Lynne Rokita, Childrens Hospital of Philadelphia; Priya Khurana, Childrens Hospital of Philadelphia; Selma M. Cuya, Emory University; Kristopher R. Bosse, Childrens Hospital of Philadelphia; Adeiye Pilgrim, Emory University; Daisy Li, Emory University; Cara Shields, Emory University; Oskar Laur, Emory University; John M. Maris, Childrens Hospital of Philadelphia; Robert Schnepp, Emory University
• Language: English
• Date: 2020-06-01
• Publisher: ELSEVIER SCIENCE INC
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neo.2020.04.001
• Title of Journal or Parent Work: NEOPLASIA
• Volume: 22
• Issue: 6
• Start Page: 231
• End Page: 241
• Grant/Funding Information: Of note, the Emory Integrated Genomics Core is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities.; This work was supported in part by NIH Grant K08-7K08CA194162-02 (R.W.S.), NIH Grant R35 CA220500 (J.M.M.), NIH Grant R01 CA124709 (J.M.M.), the Alex’s Lemonade Stand Foundation (J.L.R., K.R.B., R.W.S.), the Damon Runyon Cancer Research Foundation (PST-07-16; K.R.B.), Hyundai Hope on Wheels (R.W.S.), Andrew McDonough B + Foundation (R.W.S.), Team Connor Foundation (R.W.S.), Rally Foundation for Childhood Cancer Research (R.W.S.), the Winship Cancer Institute American Cancer Society Institutional Research Grant (R.W.S.), the Aflac Cancer and Blood Disorders Center Trust (R.W.S.), and the William Woods, M.D., Aflac Clinical Investigator Chair (R.W.S.).; Additional support was provided by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454.
• Keywords: CANCER; Oncology; EXPRESSION; SELF-RENEWAL; PBK/TOPK; GENES; Life Sciences & Biomedicine; Neuroblastoma; PDZ binding kinase; STAGE; GROWTH; Science & Technology; Metastasis; TARGETING MYCN; MODEL; LIN28B; Let-7; INHIBITOR
• Research Categories: Biology, Neuroscience; Health Sciences, Oncology

Abstract

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.