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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
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| Enthalten in: |
Neoplasia (New York, N.Y.) - 22(2020), 6 vom: 24. Apr., Seite 231-241 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Dongdong [VerfasserIn] |
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| Links: |
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| Themen: |
Journal Article |
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| Anmerkungen: |
Date Revised 27.02.2024 published: Print-Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.neo.2020.04.001 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM309240034 |
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| 520 | |a Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a LIN28B | |
| 650 | 4 | |a Let-7 | |
| 650 | 4 | |a Metastasis | |
| 650 | 4 | |a Neuroblastoma | |
| 650 | 4 | |a PDZ binding kinase | |
| 700 | 1 | |a Cox, Julie |e verfasserin |4 aut | |
| 700 | 1 | |a Annam, Jayabhargav |e verfasserin |4 aut | |
| 700 | 1 | |a Weingart, Melanie |e verfasserin |4 aut | |
| 700 | 1 | |a Essien, Grace |e verfasserin |4 aut | |
| 700 | 1 | |a Rathi, Komal S |e verfasserin |4 aut | |
| 700 | 1 | |a Rokita, Jo Lynne |e verfasserin |4 aut | |
| 700 | 1 | |a Khurana, Priya |e verfasserin |4 aut | |
| 700 | 1 | |a Cuya, Selma M |e verfasserin |4 aut | |
| 700 | 1 | |a Bosse, Kristopher R |e verfasserin |4 aut | |
| 700 | 1 | |a Pilgrim, Adeiye |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Daisy |e verfasserin |4 aut | |
| 700 | 1 | |a Shields, Cara |e verfasserin |4 aut | |
| 700 | 1 | |a Laur, Oskar |e verfasserin |4 aut | |
| 700 | 1 | |a Maris, John M |e verfasserin |4 aut | |
| 700 | 1 | |a Schnepp, Robert W |e verfasserin |4 aut | |
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