Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells
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 o...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/8/1909 |
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| author | Joachim T. Siaw Jonatan L. Gabre Ezgi Uçkun Marc Vigny Wancun Zhang Jimmy Van den Eynden Bengt Hallberg Ruth H. Palmer Jikui Guan |
| author_facet | Joachim T. Siaw Jonatan L. Gabre Ezgi Uçkun Marc Vigny Wancun Zhang Jimmy Van den Eynden Bengt Hallberg Ruth H. Palmer Jikui Guan |
| author_sort | Joachim T. Siaw |
| collection | DOAJ |
| description | 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, <i>RET</i> knockout (KO) SK-N-AS cells were generated by CRISPR/Cas9 genome engineering. Gene expression analysis of <i>RET</i> 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. |
| first_indexed | 2024-03-10T12:17:18Z |
| format | Article |
| id | doaj.art-61061a11b5bb4c9eb230c207089ae54f |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T12:17:18Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-61061a11b5bb4c9eb230c207089ae54f2023-11-21T15:44:13ZengMDPI AGCancers2072-66942021-04-01138190910.3390/cancers13081909Loss of RET Promotes Mesenchymal Identity in Neuroblastoma CellsJoachim T. Siaw0Jonatan L. Gabre1Ezgi Uçkun2Marc Vigny3Wancun Zhang4Jimmy Van den Eynden5Bengt Hallberg6Ruth H. Palmer7Jikui Guan8Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, SwedenDepartment of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, SwedenDepartment of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, SwedenUniversité Pierre et Marie Curie, UPMC, INSERM UMRS-839, 75005 Paris, FranceDepartment of Pediatric Oncology Surgery, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, ChinaAnatomy and Embryology Unit, Department of Human Structure and Repair, Ghent University, 9000 Ghent, BelgiumDepartment of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, SwedenDepartment of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, SwedenDepartment of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, SwedenAberrant 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, <i>RET</i> knockout (KO) SK-N-AS cells were generated by CRISPR/Cas9 genome engineering. Gene expression analysis of <i>RET</i> 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.https://www.mdpi.com/2072-6694/13/8/1909ALKALKAL2EMTneural differentiationadrenergicretinoic acid |
| spellingShingle | Joachim T. Siaw Jonatan L. Gabre Ezgi Uçkun Marc Vigny Wancun Zhang Jimmy Van den Eynden Bengt Hallberg Ruth H. Palmer Jikui Guan Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells Cancers ALK ALKAL2 EMT neural differentiation adrenergic retinoic acid |
| title | Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells |
| title_full | Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells |
| title_fullStr | Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells |
| title_full_unstemmed | Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells |
| title_short | Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells |
| title_sort | loss of ret promotes mesenchymal identity in neuroblastoma cells |
| topic | ALK ALKAL2 EMT neural differentiation adrenergic retinoic acid |
| url | https://www.mdpi.com/2072-6694/13/8/1909 |
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