Neural crest-related NXPH1/α-NRXN signaling opposes neuroblastoma malignancy by inhibiting metastasis

Fanlo-Escudero, L.; Gomez-Gonzalez, S.; Sangrador, I.; Gautier, E. L.; Usieto, S.; Rebollo, E.; Vila-Ubach, M.; Carcaboso, A. M.; Celia-Terrassa, T.; Lavarino, C.; Marti, E.; Le Dreau, G.

doi:10.1101/2021.11.26.470092

bioRxiv · 10.1101/2021.11.26.470092

Neural crest-related NXPH1/α-NRXN signaling opposes neuroblastoma malignancy by inhibiting metastasis

Fanlo-Escudero, L.·Gomez-Gonzalez, S.·Sangrador, I.·Gautier, E. L.·Usieto, S.·Rebollo, E.·Vila-Ubach, M.·Carcaboso, A. M.·Celia-Terrassa, T.·Lavarino, C.·Marti, E.·Le Dreau, G.

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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. NBs are known to originate from alterations to cells in the sympatho-adrenal lineage derived from the neural crest, but whether LR-NBs and HR-NBs differ in the way they exploit the transcriptional program underlying their developmental origin remains unclear. Here, we compared the transcriptional landscapes of primary samples of LR-NBs, HR-NBs and human fetal adrenal gland, and thereby identified the transcriptional signature associated to NB formation that further distinguishes LR-NBs from HR-NBs. The majority of the genes comprising this signature belong to the core sympatho-adrenal developmental program, are associated with favorable patient prognosis and with diminished disease progression. The top candidate gene of this list, Neurexophilin-1 (NXPH1), encodes a ligand of the transmembrane receptors -Neurexins (-NRXNs). Our functional in vivo and in vitro assays reveal that NXPH1/-NRXN signaling has a dual impact on NB behavior: whereas NXPH1 and -NRXN1 promote NB tumor growth by stimulating cell proliferation, they conversely inhibit the ability of NB cells to form metastases. Our findings uncover a module of the neural crest-derived sympatho-adrenal developmental program that opposes neuroblastoma malignancy by impeding metastasis, and pinpoint NXPH1/-NRXN signaling as a promising target to treat HR-NBs.

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Fanlo-Escudero, L., Gomez-Gonzalez, S., Sangrador, I., Gautier, E. L., Usieto, S., Rebollo, E., Vila-Ubach, M., Carcaboso, A. M., Celia-Terrassa, T., Lavarino, C., Marti, E., Le Dreau, G.. 2021-11-27. Neural crest-related NXPH1/α-NRXN signaling opposes neuroblastoma malignancy by inhibiting metastasis. https://doi.org/10.1101/2021.11.26.470092

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