Pharmacological targeting of netrin-1 inhibits EMT in cancer.

1. Nature. 2023 Aug;620(7973):402-408. doi: 10.1038/s41586-023-06372-2. Epub 2023 Aug 2. Pharmacological targeting of netrin-1 inhibits EMT in cancer. Lengrand J(#)(1)(2)(3), Pastushenko I(#)(1), Vanuytven S(#)(4)(5), Song Y(1), Venet D(6), Sarate RM(1), Bellina M(2)(3), Moers V(1), Boinet A(1), Sifrim A(5)(7), Rama N(3), Ducarouge B(2), Van Herck J(4), Dubois C(1), Scozzaro S(1), Lemaire S(1), Gieskes S(1), Bonni S(1), Collin A(8), Braissand N(2)(3), Allard J(8), Zindy E(8), Decaestecker C(8)(9), Sotiriou C(6), Salmon I(8)(10)(11), Mehlen P(12)(13), Voet T(4)(7), Bernet A(14)(15), Blanpain C(16)(17). Author information: (1)Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium. (2)NETRIS Pharma, Lyon, France. (3)Laboratory Apoptosis, Cancer and Development, Equipe labellisee 'La Ligue', LabEx DEVweCAN, Institute PLAsCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Lyon, France. (4)Department of Human Genetics, University of Leuven, KU Leuven, Leuven, Belgium. (5)Laboratory of Multi-omic Integrative Bioinformatics, Center for Human Genetics, KU Leuven, Leuven, Belgium. (6)Laboratory of Breast Cancer Translational Research J.-C. Heuson, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium. (7)KU Leuven Institute for Single-cell Omics, KU Leuven, Leuven, Belgium. (8)DIAPath, Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles (ULB), Jumet, Belgium. (9)Laboratory of Image Synthesis and Analysis, Ecole Polytechnique-Université libre de Bruxelles (EPB-ULB), Gosselies, Belgium. (10)Centre Universitaire Inter Régional d'Expertise en Anatomie pathologique Hospitalière (CurePath), Brussels, Belgium. (11)Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium. (12)NETRIS Pharma, Lyon, France. patrick.mehlen@lyon.unicancer.fr. (13)Laboratory Apoptosis, Cancer and Development, Equipe labellisee 'La Ligue', LabEx DEVweCAN, Institute PLAsCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Lyon, France. patrick.mehlen@lyon.unicancer.fr. (14)NETRIS Pharma, Lyon, France. agnes.bernet@lyon.unicancer.fr. (15)Laboratory Apoptosis, Cancer and Development, Equipe labellisee 'La Ligue', LabEx DEVweCAN, Institute PLAsCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Lyon, France. agnes.bernet@lyon.unicancer.fr. (16)Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium. cedric.blanpain@ulb.be. (17)WEL (Wallon ExceLlence) Research Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium. cedric.blanpain@ulb.be. (#)Contributed equally Comment in Nat Rev Drug Discov. 2023 Oct;22(10):785. doi: 10.1038/d41573-023-00137-2. Epithelial-to-mesenchymal transition (EMT) regulates tumour initiation, progression, metastasis and resistance to anti-cancer therapy1-7. Although great progress has been made in understanding the role of EMT and its regulatory mechanisms in cancer, no therapeutic strategy to pharmacologically target EMT has been identified. Here we found that netrin-1 is upregulated in a primary mouse model of skin squamous cell carcinoma (SCC) exhibiting spontaneous EMT. Pharmacological inhibition of netrin-1 by administration of NP137, a netrin-1-blocking monoclonal antibody currently used in clinical trials in human cancer (ClinicalTrials.gov identifier NCT02977195 ), decreased the proportion of EMT tumour cells in skin SCC, decreased the number of metastases and increased the sensitivity of tumour cells to chemotherapy. Single-cell RNA sequencing revealed the presence of different EMT states, including epithelial, early and late hybrid EMT, and full EMT states, in control SCC. By contrast, administration of NP137 prevented the progression of cancer cells towards a late EMT state and sustained tumour epithelial states. Short hairpin RNA knockdown of netrin-1 and its receptor UNC5B in EPCAM+ tumour cells inhibited EMT in vitro in the absence of stromal cells and regulated a common gene signature that promotes tumour epithelial state and restricts EMT. To assess the relevance of these findings to human cancers, we treated mice transplanted with the A549 human cancer cell line-which undergoes EMT following TGFβ1 administration8,9-with NP137. Netrin-1 inhibition decreased EMT in these transplanted A549 cells. Together, our results identify a pharmacological strategy for targeting EMT in cancer, opening up novel therapeutic interventions for anti-cancer therapy. © 2023. The Author(s), under exclusive licence to Springer Nature Limited. DOI: 10.1038/s41586-023-06372-2 PMCID: PMC7615210 PMID: 37532929 [Indexed for MEDLINE] Conflict of interest statement: Competing interests A. Bernet and P.M. declare a conflict of interest as founders and shareholders of NETRIS Pharma. J.L., P.M.