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Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells

Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, Sweden
Anatomy and Embryology Unit, Department of Human Structure and Repair, Ghent University, 9000 Ghent, Belgium
Université Pierre et Marie Curie, UPMC, INSERM UMRS-839, 75005 Paris, France
Department of Pediatric Oncology Surgery, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, China
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Roberto Chiarle
Cancers 2021, 13(8), 1909;
Received: 31 January 2021 / Revised: 21 March 2021 / Accepted: 12 April 2021 / Published: 15 April 2021
The anaplastic lymphoma kinase (ALK) and rearranged during transfection (RET) receptor tyrosine kinases (RTKs) are expressed in both the developing neural crest and the pediatric cancer neuroblastoma. Moreover, ALK is mutated in approximately 10% of neuroblastomas. Here, we investigated ALK and RET in neuroblastoma, with the aim of better understanding their respective contributions. Using neuroblastoma cell lines, we show that ALK modulates RET signaling at the level of RET phosphorylation, as well as at the level of transcription. Using CRISPR/Cas9, we generated RET knockout neuroblastoma cell lines and performed a multi-omics approach, combining RNA-Seq and proteomics to characterize the effect of deleting RET in a neuroblastoma context. Remarkably, we could show that loss of RET results in a striking epithelial-to-mesenchymal transition (EMT) phenotype, and we provide evidence that RET activity suppresses the mesenchymal phenotype in neuroblastoma.
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. View Full-Text
Keywords: ALK; ALKAL2; EMT; neural differentiation; adrenergic; retinoic acid ALK; ALKAL2; EMT; neural differentiation; adrenergic; retinoic acid
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MDPI and ACS Style

Siaw, J.T.; Gabre, J.L.; Uçkun, E.; Vigny, M.; Zhang, W.; Van den Eynden, J.; Hallberg, B.; Palmer, R.H.; Guan, J. Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells. Cancers 2021, 13, 1909.

AMA Style

Siaw JT, Gabre JL, Uçkun E, Vigny M, Zhang W, Van den Eynden J, Hallberg B, Palmer RH, Guan J. Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells. Cancers. 2021; 13(8):1909.

Chicago/Turabian Style

Siaw, Joachim T., Jonatan L. Gabre, Ezgi Uçkun, Marc Vigny, Wancun Zhang, Jimmy Van den Eynden, Bengt Hallberg, Ruth H. Palmer, and Jikui Guan. 2021. "Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells" Cancers 13, no. 8: 1909.

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