1. Neural crest-related NXPH1/α-NRXN signaling opposes neuroblastoma malignancy by inhibiting organotropic metastasis
- Author
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Fanlo, Lucía, Gómez-González, Soledad, Rozalén, Catalina, Pérez-Núñez, Iván, Sangrador, Irene, Tomás-Daza, Laureano, Gautier, Emmanuel L., Usieto, Susana, Rebollo, Elena, Vila-Ubach, Mònica, Carcaboso, Angel M., Javierre, Biola M., Celià-Terrassa, Toni, Lavarino, Cinzia, Martí, Elisa, and Le Dréau, Gwenvael
- Abstract
Neuroblastoma is a pediatric cancer that can present as low- or high-risk tumors (LR-NBs and HR-NBs), the latter group showing poor prognosis due to metastasis and strong resistance to current therapy. Whether LR-NBs and HR-NBs differ in the way they exploit the transcriptional program underlying their neural crest, sympatho-adrenal origin remains unclear. Here, we identified the transcriptional signature distinguishing LR-NBs from HR-NBs, which consists mainly of genes that belong to the core sympatho-adrenal developmental program and are associated with favorable patient prognosis and with diminished disease progression. Gain- and loss-of-function experiments revealed that the top candidate gene of this signature, Neurexophilin-1 (NXPH1), has a dual impact on NB cell behavior in vivo: whereas NXPH1 and its receptor α-NRXN1 promote NB tumor growth by stimulating cell proliferation, they conversely inhibit organotropic colonization and metastasis. As suggested by RNA-seq analyses, these effects might result from the ability of NXPH1/α-NRXN signalling to restrain the conversion of NB cells from an adrenergic state to a mesenchymal one. Our findings thus uncover a transcriptional module of the sympatho-adrenal program that opposes neuroblastoma malignancy by impeding metastasis, and pinpoint NXPH1/α-NRXN signaling as a promising target to treat HR-NBs.
- Published
- 2023
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