Journal Article

DKFZ-2025-01142

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Sonic hedgehog medulloblastomas are dependent on Netrin-1 for survival.

Talbot, J. ; Fombonne, J. ; Torrejon, J. ; Babcock, B. R. ; McSwain, L. F. ; Rama, N. ; Lospinoso Severini, L. ; Bonerandi, E. ; Marsaud, V. ; Bernardi, F. ; Gharsalli, T. ; Guix, C. ; Ducarouge, B. ; Neururer, V. ; Basili, I. ; Mercier, A. L. ; Yu, H. ; Forget, A. ; Indersie, E. ; Leboucher, S. ; Souphron, J. ; Okonechnikov, K.DKFZ* ; Wang, W. ; Kawauchi, D. ; Wainwright, B. J. ; Frappaz, D. ; Varlet, P. ; Dufour, C. ; Beccaria, K. ; Blauwblomme, T. ; Martignetti, L. ; Di Marcotullio, L. ; Puget, S. ; Doz, F. ; Bourdeaut, F. ; Masliah-Planchon, J. ; Gershon, T. R. ; Mehlen, P. ; Ayrault, O.

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-59612-6

Abstract: Netrin-1 signaling is an essential prototypical neuronal guidance mechanism during embryonic development that also regulates tumor cell survival in a variety of adult cancer entities. In line with these data, a monoclonal netrin-1 blocking antibody (anti-netrin-1 mAb/NP137) has been preclinically developed and netrin-1 blockade has recently been investigated in phase 1 and 2 clinical trials in several adult cancers. Here, we investigate the role of netrin-1 in the most common malignant pediatric brain cancer, Medulloblastoma. Interestingly, we find that netrin-1 is upregulated in medulloblastoma subgroups associated with developmental dysregulation, in particular in medulloblastoma with Sonic Hedgehog (SHH) activation. First, we demonstrate that genetic deletion of netrin-1 or systemic treatment with the clinical-stage anti-netrin-1 blocking antibody significantly reduces tumor growth in vivo in various orthotopic models of SHH medulloblastomas. Second, in vitro and in vivo, we unexpectedly uncover that SHH medulloblastomas treated with an SHH-inhibitor targeting Smoothened (SMO) increase netrin-1 expression, paving the way for combinatorial therapy. In line with that, we next show that netrin-1 blockade potentiates the efficacy of SMO inhibitor therapy in vivo. Together, our data indicate that, netrin-1 blockade, used as monotherapy or in combination with SMO inhibitors, is a promising therapeutic strategy in SHH medulloblastomas.

Keyword(s): Netrin-1: metabolism (MeSH) ; Netrin-1: genetics (MeSH) ; Netrin-1: antagonists & inhibitors (MeSH) ; Medulloblastoma: metabolism (MeSH) ; Medulloblastoma: genetics (MeSH) ; Medulloblastoma: pathology (MeSH) ; Medulloblastoma: drug therapy (MeSH) ; Hedgehog Proteins: metabolism (MeSH) ; Hedgehog Proteins: genetics (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Cell Line, Tumor (MeSH) ; Smoothened Receptor: antagonists & inhibitors (MeSH) ; Smoothened Receptor: metabolism (MeSH) ; Cerebellar Neoplasms: metabolism (MeSH) ; Cerebellar Neoplasms: genetics (MeSH) ; Cerebellar Neoplasms: pathology (MeSH) ; Cerebellar Neoplasms: drug therapy (MeSH) ; Signal Transduction (MeSH) ; Cell Survival: drug effects (MeSH) ; Tumor Suppressor Proteins: metabolism (MeSH) ; Tumor Suppressor Proteins: genetics (MeSH) ; Gene Expression Regulation, Neoplastic (MeSH) ; Female (MeSH) ; Netrin-1 ; Hedgehog Proteins ; NTN1 protein, human ; Smoothened Receptor ; Ntn1 protein, mouse ; Tumor Suppressor Proteins ; SHH protein, human

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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