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
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.