LIN28B-PDZ Binding Kinase Signaling Promotes Neuroblastoma Metastasis
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, opposes the effects of LIN28B. 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-7 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..
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Preprint| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
bioRxiv.org - (2021) vom: 15. Dez. Zur Gesamtaufnahme - year:2021 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Dongdong [VerfasserIn] |
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| Links: |
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| doi: |
10.1101/742262 |
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| funding: |
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| PPN (Katalog-ID): |
XBI000598313 |
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| 520 | |a 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, opposes the effects of LIN28B. 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-7 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. | ||
| 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 | |
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| 700 | 1 | |a Li, Daisy |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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