2. Academic Validation
  3. Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells

Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells

  • Cancers (Basel). 2021 Apr 15;13(8):1909. doi: 10.3390/cancers13081909.
Joachim T Siaw 1,  Jonatan L Gabre 1 2,  Ezgi Uçkun 1,  Marc Vigny 3,  Wancun Zhang 4,  Jimmy Van den Eynden 2,  Bengt Hallberg 1,  Ruth H Palmer 1,  Jikui Guan 1 4
Affiliations

Affiliations

  • 1 Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, Sweden.
  • 2 Anatomy and Embryology Unit, Department of Human Structure and Repair, Ghent University, 9000 Ghent, Belgium.
  • 3 Université Pierre et Marie Curie, UPMC, INSERM UMRS-839, 75005 Paris, France.
  • 4 Department of Pediatric Oncology Surgery, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, China.
PMID: 33921066 DOI: 10.3390/cancers13081909
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 knockout (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 development. 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.

Keywords

ALK; ALKAL2; EMT; adrenergic; neural differentiation; retinoic acid.

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