Pharmacological targeting of netrin-1 inhibits EMT in cancer

Justine Lengrand, Ievgenia Pastushenko, Sebastiaan Vanuytven, Yura Song, David Venet, Rahul M. Sarate, Melanie Bellina, Virginie Moers, Alice Boinet, Alejandro Sifrim, Nicolas Rama, Benjamin Ducarouge, Jens Van Herck, Christine Dubois, Samuel Scozzaro, Sophie Lemaire, Sarah Gieskes, Sophie Bonni, Amandine Collin, Nicolas Braissand, Justine Allard, Egor Zindy, Christine Decaestecker, Christos Sotiriou, Isabelle Salmon, Patrick Mehlen (), Thierry Voet, Agnès Bernet () and Cédric Blanpain ()
Additional contact information
Justine Lengrand: Université Libre de Bruxelles (ULB)
Ievgenia Pastushenko: Université Libre de Bruxelles (ULB)
Sebastiaan Vanuytven: University of Leuven, KU Leuven
Yura Song: Université Libre de Bruxelles (ULB)
David Venet: Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB)
Rahul M. Sarate: Université Libre de Bruxelles (ULB)
Melanie Bellina: NETRIS Pharma
Virginie Moers: Université Libre de Bruxelles (ULB)
Alice Boinet: Université Libre de Bruxelles (ULB)
Alejandro Sifrim: KU Leuven
Nicolas Rama: INSERM U1052-CNRS UMR5286
Benjamin Ducarouge: NETRIS Pharma
Jens Van Herck: University of Leuven, KU Leuven
Christine Dubois: Université Libre de Bruxelles (ULB)
Samuel Scozzaro: Université Libre de Bruxelles (ULB)
Sophie Lemaire: Université Libre de Bruxelles (ULB)
Sarah Gieskes: Université Libre de Bruxelles (ULB)
Sophie Bonni: Université Libre de Bruxelles (ULB)
Amandine Collin: Université Libre de Bruxelles (ULB)
Nicolas Braissand: NETRIS Pharma
Justine Allard: Université Libre de Bruxelles (ULB)
Egor Zindy: Université Libre de Bruxelles (ULB)
Christine Decaestecker: Université Libre de Bruxelles (ULB)
Christos Sotiriou: Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB)
Isabelle Salmon: Université Libre de Bruxelles (ULB)
Patrick Mehlen: NETRIS Pharma
Thierry Voet: University of Leuven, KU Leuven
Agnès Bernet: NETRIS Pharma
Cédric Blanpain: Université Libre de Bruxelles (ULB)

Nature, 2023, vol. 620, issue 7973, 402-408

Abstract: Abstract 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.

Date: 2023
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-023-06372-2 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:620:y:2023:i:7973:d:10.1038_s41586-023-06372-2

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-06372-2

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().