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Loss of ret promotes mesenchymal identity in neuroblastoma cells

Siaw, Joachim T. LU orcid ; Gabre, Jonatan L. ; Uçkun, Ezgi ; Vigny, Marc ; Zhang, Wancun ; Van den Eynden, Jimmy ; Hallberg, Bengt ; Palmer, Ruth H. and Guan, Jikui (2021) In Cancers 13(8).
Abstract

Aberrant activation of anaplastic lymphoma kinase (ALK) drives neuroblastoma (NB). Previous work identified the RET receptor tyrosine kinase (RTK) as a downstream target of ALK activity in NB models. We show here that ALK activation in response to ALKAL2 ligand results in the rapid phosphorylation of RET in NB cells, providing additional insight into the contribution of RET to the ALK-driven gene signature in NB. To further address the role of RET in NB, RET knock-out (KO) SK-N-AS cells were generated by CRISPR/Cas9 genome engineering. Gene expression analysis of RET KO NB cells identified a reprogramming of NB cells to a mesenchymal (MES) phenotype that was characterized by increased migration and upregulation of the AXL and MNNG HOS... (More)

Aberrant activation of anaplastic lymphoma kinase (ALK) drives neuroblastoma (NB). Previous work identified the RET receptor tyrosine kinase (RTK) as a downstream target of ALK activity in NB models. We show here that ALK activation in response to ALKAL2 ligand results in the rapid phosphorylation of RET in NB cells, providing additional insight into the contribution of RET to the ALK-driven gene signature in NB. To further address the role of RET in NB, RET knock-out (KO) SK-N-AS cells were generated by CRISPR/Cas9 genome engineering. Gene expression analysis of RET KO NB cells identified a reprogramming of NB cells to a mesenchymal (MES) phenotype that was characterized by increased migration and upregulation of the AXL and MNNG HOS transforming gene (MET) RTKs, as well as integrins and extracellular matrix components. Strikingly, the upregulation of AXL in the absence of RET reflects the development timeline observed in the neural crest as progenitor cells undergo differentiation during embryonic develop-ment. Together, these findings suggest that a MES phenotype is promoted in mesenchymal NB cells in the absence of RET, reflective of a less differentiated developmental status.

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author
; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adrenergic, ALK, ALKAL2, EMT, Neural differentiation, Retinoic acid
in
Cancers
volume
13
issue
8
article number
1909
publisher
MDPI AG
external identifiers
  • scopus:85104149124
ISSN
2072-6694
DOI
10.3390/cancers13081909
language
English
LU publication?
no
additional info
Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
id
c41977dc-4b35-49be-8cf0-a6e31705a4ee
date added to LUP
2025-03-19 11:47:04
date last changed
2025-04-04 14:08:16
@article{c41977dc-4b35-49be-8cf0-a6e31705a4ee,
  abstract     = {{<p>Aberrant activation of anaplastic lymphoma kinase (ALK) drives neuroblastoma (NB). Previous work identified the RET receptor tyrosine kinase (RTK) as a downstream target of ALK activity in NB models. We show here that ALK activation in response to ALKAL2 ligand results in the rapid phosphorylation of RET in NB cells, providing additional insight into the contribution of RET to the ALK-driven gene signature in NB. To further address the role of RET in NB, RET knock-out (KO) SK-N-AS cells were generated by CRISPR/Cas9 genome engineering. Gene expression analysis of RET KO NB cells identified a reprogramming of NB cells to a mesenchymal (MES) phenotype that was characterized by increased migration and upregulation of the AXL and MNNG HOS transforming gene (MET) RTKs, as well as integrins and extracellular matrix components. Strikingly, the upregulation of AXL in the absence of RET reflects the development timeline observed in the neural crest as progenitor cells undergo differentiation during embryonic develop-ment. Together, these findings suggest that a MES phenotype is promoted in mesenchymal NB cells in the absence of RET, reflective of a less differentiated developmental status.</p>}},
  author       = {{Siaw, Joachim T. and Gabre, Jonatan L. and Uçkun, Ezgi and Vigny, Marc and Zhang, Wancun and Van den Eynden, Jimmy and Hallberg, Bengt and Palmer, Ruth H. and Guan, Jikui}},
  issn         = {{2072-6694}},
  keywords     = {{Adrenergic; ALK; ALKAL2; EMT; Neural differentiation; Retinoic acid}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{8}},
  publisher    = {{MDPI AG}},
  series       = {{Cancers}},
  title        = {{Loss of ret promotes mesenchymal identity in neuroblastoma cells}},
  url          = {{http://dx.doi.org/10.3390/cancers13081909}},
  doi          = {{10.3390/cancers13081909}},
  volume       = {{13}},
  year         = {{2021}},
}