Open AccessTargeting netrin‐3 in small cell lung cancer and neuroblastoma
Author(s) -
Jiang Shan,
Richaud Mathieu,
Vieugué Pauline,
Rama Nicolas,
Delcros JeanGuy,
Siouda Maha,
Sanada Mitsuaki,
Redavid AnnaRita,
Ducarouge Benjamin,
Hervieu Maëva,
Breusa Silvia,
Manceau Ambroise,
Gattolliat CharlesHenry,
Gadot Nicolas,
Combaret Valérie,
Neves David,
OrtizCuaran Sandra,
Saintigny Pierre,
Meurette Olivier,
Walter Thomas,
JanoueixLerosey Isabelle,
Hofman Paul,
Mulligan Peter,
Goldshneider David,
Mehlen Patrick,
Gibert Benjamin
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202012878
Subject(s) - medicine , humanities , library science , art , computer science
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.