LIN28B promotes neuroblastoma metastasis and regulates PDZ binding kinase

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved..

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.

Media Type:

Electronic Article

Year of Publication:

2020

Contained In:

Neoplasia (New York, N.Y.) - Vol. 22, No. 6 (2020), p. 231-241

Language:

English

Contributors:

Chen, Dongdong
Cox, Julie
Annam, Jayabhargav
Weingart, Melanie
Essien, Grace
Rathi, Komal S
Rokita, Jo Lynne
Khurana, Priya
Cuya, Selma M
Bosse, Kristopher R
Pilgrim, Adeiye
Li, Daisy
Shields, Cara
Laur, Oskar
Maris, John M
Schnepp, Robert W

Links:

Volltext

Keywords:

Journal Article
LIN28B
Let-7
Metastasis
Neuroblastoma
PDZ binding kinase

Notes:

Date Revised 10.01.2021

published: Print-Electronic

Citation Status Publisher

Copyright: From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Physical Description:

Online-Ressource

doi:

10.1016/j.neo.2020.04.001

PMID:

32339949

PPN (Catalogue-ID):

NLM310097975