EMBO Molecular Medicine (Apr 2021)
Targeting netrin‐3 in small cell lung cancer and neuroblastoma
- Shan Jiang,
- Mathieu Richaud,
- Pauline Vieugué,
- Nicolas Rama,
- Jean‐Guy Delcros,
- Maha Siouda,
- Mitsuaki Sanada,
- Anna‐Rita Redavid,
- Benjamin Ducarouge,
- Maëva Hervieu,
- Silvia Breusa,
- Ambroise Manceau,
- Charles‐Henry Gattolliat,
- Nicolas Gadot,
- Valérie Combaret,
- David Neves,
- Sandra Ortiz‐Cuaran,
- Pierre Saintigny,
- Olivier Meurette,
- Thomas Walter,
- Isabelle Janoueix‐Lerosey,
- Paul Hofman,
- Peter Mulligan,
- David Goldshneider,
- Patrick Mehlen,
- Benjamin Gibert
Affiliations
- Shan Jiang
- Apoptosis, Cancer and Development Laboratory‐ Equipe labellisée ‘La Ligue’ LabEx DEVweCAN Institut PLAsCAN Centre de Recherche en Cancérologie de Lyon INSERM U1052‐CNRS UMR5286 Université de LyonCentre Léon Bérard Lyon France
- Mathieu Richaud
- Apoptosis, Cancer and Development Laboratory‐ Equipe labellisée ‘La Ligue’ LabEx DEVweCAN Institut PLAsCAN Centre de Recherche en Cancérologie de Lyon INSERM U1052‐CNRS UMR5286 Université de LyonCentre Léon Bérard Lyon France
- Pauline Vieugué
- Apoptosis, Cancer and Development Laboratory‐ Equipe labellisée ‘La Ligue’ LabEx DEVweCAN Institut PLAsCAN Centre de Recherche en Cancérologie de Lyon INSERM U1052‐CNRS UMR5286 Université de LyonCentre Léon Bérard Lyon France
- Nicolas Rama
- Apoptosis, Cancer and Development Laboratory‐ Equipe labellisée ‘La Ligue’ LabEx DEVweCAN Institut PLAsCAN Centre de Recherche en Cancérologie de Lyon INSERM U1052‐CNRS UMR5286 Université de LyonCentre Léon Bérard Lyon France
- Jean‐Guy Delcros
- Apoptosis, Cancer and Development Laboratory‐ Equipe labellisée ‘La Ligue’ LabEx DEVweCAN Institut PLAsCAN Centre de Recherche en Cancérologie de Lyon INSERM U1052‐CNRS UMR5286 Université de LyonCentre Léon Bérard Lyon France
- Maha Siouda
- Univ LyonCentre Léon BérardCentre de Recherche en Cancérologie de LyonUniversité Claude Bernard Lyon 1INSERM 1052CNRS 5286 Lyon France
- Mitsuaki Sanada
- Toray Industries, Inc.New Frontiers Research Labs Kanagawa Japan
- Anna‐Rita Redavid
- Apoptosis, Cancer and Development Laboratory‐ Equipe labellisée ‘La Ligue’ LabEx DEVweCAN Institut PLAsCAN Centre de Recherche en Cancérologie de Lyon INSERM U1052‐CNRS UMR5286 Université de LyonCentre Léon Bérard Lyon France
- Benjamin Ducarouge
- Netris Pharma Lyon France
- Maëva Hervieu
- Apoptosis, Cancer and Development Laboratory‐ Equipe labellisée ‘La Ligue’ LabEx DEVweCAN Institut PLAsCAN Centre de Recherche en Cancérologie de Lyon INSERM U1052‐CNRS UMR5286 Université de LyonCentre Léon Bérard Lyon France
- Silvia Breusa
- Apoptosis, Cancer and Development Laboratory‐ Equipe labellisée ‘La Ligue’ LabEx DEVweCAN Institut PLAsCAN Centre de Recherche en Cancérologie de Lyon INSERM U1052‐CNRS UMR5286 Université de LyonCentre Léon Bérard Lyon France
- Ambroise Manceau
- Apoptosis, Cancer and Development Laboratory‐ Equipe labellisée ‘La Ligue’ LabEx DEVweCAN Institut PLAsCAN Centre de Recherche en Cancérologie de Lyon INSERM U1052‐CNRS UMR5286 Université de LyonCentre Léon Bérard Lyon France
- Charles‐Henry Gattolliat
- CNRS UMR 8126University Paris‐Sud 11Institut Gustave Roussy Villejuif France
- Nicolas Gadot
- Centre de Recherche en Cancérologie de LyonCentre Léon Bérard Lyon France
- Valérie Combaret
- Centre de Recherche en Cancérologie de LyonCentre Léon Bérard Lyon France
- David Neves
- Netris Pharma Lyon France
- Sandra Ortiz‐Cuaran
- Univ LyonCentre Léon BérardCentre de Recherche en Cancérologie de LyonUniversité Claude Bernard Lyon 1INSERM 1052CNRS 5286 Lyon France
- Pierre Saintigny
- Univ LyonCentre Léon BérardCentre de Recherche en Cancérologie de LyonUniversité Claude Bernard Lyon 1INSERM 1052CNRS 5286 Lyon France
- Olivier Meurette
- Apoptosis, Cancer and Development Laboratory‐ Equipe labellisée ‘La Ligue’ LabEx DEVweCAN Institut PLAsCAN Centre de Recherche en Cancérologie de Lyon INSERM U1052‐CNRS UMR5286 Université de LyonCentre Léon Bérard Lyon France
- Thomas Walter
- Apoptosis, Cancer and Development Laboratory‐ Equipe labellisée ‘La Ligue’ LabEx DEVweCAN Institut PLAsCAN Centre de Recherche en Cancérologie de Lyon INSERM U1052‐CNRS UMR5286 Université de LyonCentre Léon Bérard Lyon France
- Isabelle Janoueix‐Lerosey
- INSERMU830Génétique et Biologie des CancersInstitut Curie Paris France
- Paul Hofman
- Laboratory of Clinical and Experimental Pathology Université Côte d'AzurCHU NiceFHU OncoAgePasteur Hospital Nice France
- Peter Mulligan
- Univ LyonCentre Léon BérardCentre de Recherche en Cancérologie de LyonUniversité Claude Bernard Lyon 1INSERM 1052CNRS 5286 Lyon France
- David Goldshneider
- Netris Pharma Lyon France
- Patrick Mehlen
- Apoptosis, Cancer and Development Laboratory‐ Equipe labellisée ‘La Ligue’ LabEx DEVweCAN Institut PLAsCAN Centre de Recherche en Cancérologie de Lyon INSERM U1052‐CNRS UMR5286 Université de LyonCentre Léon Bérard Lyon France
- Benjamin Gibert
- Apoptosis, Cancer and Development Laboratory‐ Equipe labellisée ‘La Ligue’ LabEx DEVweCAN Institut PLAsCAN Centre de Recherche en Cancérologie de Lyon INSERM U1052‐CNRS UMR5286 Université de LyonCentre Léon Bérard Lyon France
- DOI
- https://doi.org/10.15252/emmm.202012878
- Journal volume & issue
-
Vol. 13,
no. 4
pp. n/a – n/a
Abstract
Abstract The navigation cue netrin‐1 is well‐documented for its key role in cancer development and represents a promising therapeutic target currently under clinical investigation. Phase 1 and 2 clinical trials are ongoing with NP137, a humanized monoclonal antibody against netrin‐1. Interestingly, the epitope recognized by NP137 in netrin‐1 shares 90% homology with its counterpart in netrin‐3, the closest member to netrin‐1 in humans, for which little is known in the field of cancer. Here, we unveiled that netrin‐3 appears to be expressed specifically in human neuroblastoma (NB) and small cell lung cancer (SCLC), two subtypes of neuroectodermal/neuroendocrine lineages. Netrin‐3 and netrin‐1 expression are mutually exclusive, and the former is driven by the MYCN oncogene in NB, and the ASCL‐1 or NeuroD1 transcription factors in SCLC. Netrin‐3 expression is correlated with disease stage, aggressiveness, and overall survival in NB. Mechanistically, we confirmed the high affinity of netrin‐3 for netrin‐1 receptors and we demonstrated that netrin‐3 genetic silencing or interference using NP137, delayed tumor engraftment, and reduced tumor growth in animal models. Altogether, these data support the targeting of netrin‐3 in NB and SCLC.
Keywords