Sonic hedgehog medulloblastomas are dependent on Netrin-1 for survival

Julie Talbot, Joanna Fombonne, Jacob Torrejon, Benjamin R. Babcock, Leon F. McSwain, Nicolas Rama, Ludovica Lospinoso Severini, Emma Bonerandi, Veronique Marsaud, Flavia Bernardi, Tarek Gharsalli, Catherine Guix, Benjamin Ducarouge, Verena Neururer, Irene Basili, Audrey L. Mercier, Hua Yu, Antoine Forget, Emilie Indersie, Sophie Leboucher, Judith Souphron, Konstantin Okonechnikov, Wanchen Wang, Daisuke Kawauchi, Brandon J. Wainwright, Didier Frappaz, Pascale Varlet, Christelle Dufour, Kevin Beccaria, Thomas Blauwblomme, Loredana Martignetti, Lucia Marcotullio, Stéphanie Puget, François Doz, Franck Bourdeaut, Julien Masliah-Planchon, Timothy R. Gershon, Patrick Mehlen () and Olivier Ayrault ()
Additional contact information
Julie Talbot: INSERM U1330/CNRS EMR 8001. Children’s Oncology Research Unit (CONCERT)
Joanna Fombonne: Centre Léon Bérard
Jacob Torrejon: INSERM U1330/CNRS EMR 8001. Children’s Oncology Research Unit (CONCERT)
Benjamin R. Babcock: Emory University
Leon F. McSwain: Emory University School of Medicine
Nicolas Rama: Centre Léon Bérard
Ludovica Lospinoso Severini: University La Sapienza
Emma Bonerandi: INSERM U1330/CNRS EMR 8001. Children’s Oncology Research Unit (CONCERT)
Veronique Marsaud: CNRS UMR 3347, INSERM U1021
Flavia Bernardi: INSERM U1330/CNRS EMR 8001. Children’s Oncology Research Unit (CONCERT)
Tarek Gharsalli: CNRS UMR 3347, INSERM U1021
Catherine Guix: Centre Léon Bérard
Benjamin Ducarouge: NETRIS Pharma
Verena Neururer: Centre Léon Bérard
Irene Basili: INSERM U1330/CNRS EMR 8001. Children’s Oncology Research Unit (CONCERT)
Audrey L. Mercier: CNRS UMR 3347, INSERM U1021
Hua Yu: CNRS UMR 3347, INSERM U1021
Antoine Forget: CNRS UMR 3347, INSERM U1021
Emilie Indersie: CNRS UMR 3347, INSERM U1021
Sophie Leboucher: Plateforme d’Histologie
Judith Souphron: INSERM U1330/CNRS EMR 8001. Children’s Oncology Research Unit (CONCERT)
Konstantin Okonechnikov: German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)
Wanchen Wang: National Center of Neurology and Psychiatry
Daisuke Kawauchi: National Center of Neurology and Psychiatry
Brandon J. Wainwright: The University of Queensland
Didier Frappaz: Institut d’Hématologie et Oncologie Pédiatrique et Adulte
Pascale Varlet: Sainte-Anne Hospital
Christelle Dufour: Institut Gustave-Roussy
Kevin Beccaria: Université de Paris Cité
Thomas Blauwblomme: Université de Paris Cité
Loredana Martignetti: PSL Research University, INSERM U900
Lucia Marcotullio: University La Sapienza
Stéphanie Puget: Université de Paris Cité
François Doz: Université Paris Cité
Franck Bourdeaut: Université Paris Cité
Julien Masliah-Planchon: Institut Curie
Timothy R. Gershon: Emory University School of Medicine
Patrick Mehlen: Centre Léon Bérard
Olivier Ayrault: INSERM U1330/CNRS EMR 8001. Children’s Oncology Research Unit (CONCERT)

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59612-6

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