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Sonic hedgehog medulloblastomas are dependent on Netrin-1 for survival

Author

Listed:
  • Julie Talbot

    (INSERM U1330/CNRS EMR 8001. Children’s Oncology Research Unit (CONCERT)
    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)
    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)
    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)
    INSERM U1330/CNRS EMR 8001. Children’s Oncology Research Unit (CONCERT))

  • Tarek Gharsalli

    (CNRS UMR 3347, INSERM U1021
    Inovarion)

  • 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)
    INSERM U1330/CNRS EMR 8001. Children’s Oncology Research Unit (CONCERT)
    University La Sapienza
    Sapienza University of Rome)

  • 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)
    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
    Nagoya City University)

  • Daisuke Kawauchi

    (National Center of Neurology and Psychiatry
    Nagoya City University)

  • 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
    Mines Paris Tech)

  • Lucia Marcotullio

    (University La Sapienza
    Sapienza University of Rome)

  • Stéphanie Puget

    (Université de Paris Cité)

  • François Doz

    (Université Paris Cité
    Institut Curie)

  • Franck Bourdeaut

    (Université Paris Cité
    Institut Curie
    INSERM U1330. Children’s Oncology Research Unit (CONCERT))

  • Julien Masliah-Planchon

    (Institut Curie
    Laboratory of Somatic Genetics)

  • Timothy R. Gershon

    (Emory University School of Medicine)

  • Patrick Mehlen

    (Centre Léon Bérard
    NETRIS Pharma)

  • Olivier Ayrault

    (INSERM U1330/CNRS EMR 8001. Children’s Oncology Research Unit (CONCERT)
    INSERM U1330/CNRS EMR 8001. Children’s Oncology Research Unit (CONCERT))

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.

Suggested Citation

  • Julie Talbot & Joanna Fombonne & Jacob Torrejon & Benjamin R. Babcock & Leon F. McSwain & Nicolas Rama & Ludovica Lospinoso Severini & Emma Bonerandi & Veronique Marsaud & Flavia Bernardi & Tarek Ghar, 2025. "Sonic hedgehog medulloblastomas are dependent on Netrin-1 for survival," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59612-6
    DOI: 10.1038/s41467-025-59612-6
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    References listed on IDEAS

    as
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