Sonic hedgehog medulloblastomas are dependent on Netrin-1 for survival
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.
Authors
- Christelle Dufour (ORCID: https://orcid.org/0000-0001-5993-8077)
- Franck Bourdeaut (ORCID: https://orcid.org/0000-0001-9489-6781)
- Olivier Ayrault (ORCID: https://orcid.org/0000-0002-7942-6674)
- Tarek Gharsalli (ORCID: https://orcid.org/0000-0002-4038-8447)
- Antoine Forget (ORCID: https://orcid.org/0000-0003-0223-0312)
- Konstantin Okonechnikov (ORCID: https://orcid.org/0000-0002-3409-2340)
- Émilie Indersie (ORCID: https://orcid.org/0000-0001-8974-6551)
- Brandon J. Wainwright (ORCID: https://orcid.org/0000-0003-0406-2092)
- Julie Talbot
- Thomas Blauwblomme (ORCID: https://orcid.org/0000-0003-4076-9642)
- Judith Souphron
- Hua Yu (ORCID: https://orcid.org/0009-0001-6923-9111)
- Didier Frappaz (ORCID: https://orcid.org/0000-0002-3684-9909)
- Joanna Fombonne
- Kévin Beccaria (ORCID: https://orcid.org/0000-0002-3405-1944)
- Leon McSwain
- Lucia Di Marcotullio (ORCID: https://orcid.org/0000-0003-0274-7178)
- Daisuke Kawauchi (ORCID: https://orcid.org/0000-0002-7679-173X)
- Patrick Mehlen (ORCID: https://orcid.org/0000-0003-1743-5417)
- François Doz (ORCID: https://orcid.org/0000-0001-9286-4831)
- Loredana Martignetti (ORCID: https://orcid.org/0000-0003-1535-7515)
- Catherine Guix
- Ludovica Lospinoso Severini (ORCID: https://orcid.org/0000-0002-1032-5496)
- Irene Basili (ORCID: https://orcid.org/0000-0002-5117-2529)
- Julien Masliah‐Planchon (ORCID: https://orcid.org/0000-0002-5596-3926)
- Véronique Marsaud
- Pascale Varlet (ORCID: https://orcid.org/0000-0002-8164-1517)
- Sophie Leboucher (ORCID: https://orcid.org/0000-0001-9922-8205)
- Nicolas Rama (ORCID: https://orcid.org/0000-0003-1614-7755)
- Benjamin Babcock (ORCID: https://orcid.org/0000-0002-2902-8045)
- Timothy R. Gershon (ORCID: https://orcid.org/0000-0001-7034-6400)
- Flavia Bernardi (ORCID: https://orcid.org/0000-0002-9740-2983)
- Benjamin Ducarouge (ORCID: https://orcid.org/0000-0002-6701-0508)
- Jacob Torrejón (ORCID: https://orcid.org/0000-0003-0410-6075)
- Stéphanie Puget
- Audrey Mercier
- Wan-Chen Wang (ORCID: https://orcid.org/0000-0002-4098-7482)
- Verena Neururer
- Emma Bonerandi
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Université Paris-Sud (FR)
- Hôpital Necker-Enfants Malades (FR)
- Centre National de la Recherche Scientifique (FR)
- Emory University (US)
- Inserm (FR)
- The University of Queensland (AU)
- German Cancer Research Center (DE)
- Université Paris Cité (FR)
- Heidelberg University (DE)
- Université Paris Sciences et Lettres (FR)
- Université Paris-Saclay (FR)
- Institut Gustave Roussy (FR)
- Nagoya City University (JP)
- Institut d’Hématologie et d’Oncologie Pédiatrique (FR)
- Hôpital Cochin (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Netris Pharma (France) (FR)
- National Center of Neurology and Psychiatry (JP)
- Hopp Children's Cancer Center Heidelberg (DE)
- Centre de Recherche en Cancérologie de Lyon (FR)
- FHU Neurovasc (FR)
- Istituto Pasteur (IT)
- École Nationale Supérieure des Mines de Paris (FR)
- Institut Curie (FR)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-06-03
- DOI
- https://doi.org/10.1038/s41467-025-59612-6
- Citations
- 2
- Primary Topic
- Hedgehog Signaling Pathway Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Istituto Pasteur-Fondazione Cenci Bolognetti
- Fondazione Umberto Veronesi
- Centre National de la Recherche Scientifique
- Associazione Italiana per la Ricerca sul Cancro
- Institut National Du Cancer
- Université Paris-Saclay
- LabEx DEvweCAN