Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer

Philippe A. Cassier, Raul Navaridas, Melanie Bellina, Nicolas Rama, Benjamin Ducarouge, Hector Hernandez-Vargas, Jean-Pierre Delord, Justine Lengrand, Andrea Paradisi, Laurent Fattet, Gwenaële Garin, Hanane Gheit, Cecile Dalban, Ievgenia Pastushenko, David Neves, Remy Jelin, Nicolas Gadot, Nicolas Braissand, Sophie Léon, Cyril Degletagne, Xavier Matias-Guiu, Mojgan Devouassoux-Shisheboran, Eliane Mery-Lamarche, Justine Allard, Egor Zindy, Christine Decaestecker, Isabelle Salmon, David Perol, Xavi Dolcet, Isabelle Ray-Coquard, Cédric Blanpain, Agnès Bernet () and Patrick Mehlen ()
Additional contact information
Philippe A. Cassier: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Raul Navaridas: Universidad de Lleida
Melanie Bellina: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Nicolas Rama: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Benjamin Ducarouge: Netris Pharma
Hector Hernandez-Vargas: Claude Bernard Lyon 1 University
Jean-Pierre Delord: Institut Claudius Regaud, IUCT-Oncopole
Justine Lengrand: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Andrea Paradisi: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Laurent Fattet: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Gwenaële Garin: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Hanane Gheit: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Cecile Dalban: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Ievgenia Pastushenko: Université Libre de Bruxelles
David Neves: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Remy Jelin: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Nicolas Gadot: Université Claude Bernard Lyon1, Centre Léon Bérard
Nicolas Braissand: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Sophie Léon: Université Claude Bernard Lyon1, Centre Léon Bérard
Cyril Degletagne: Université Claude Bernard Lyon1, Centre Léon Bérard
Xavier Matias-Guiu: Universidad de Lleida
Mojgan Devouassoux-Shisheboran: Hospices Civils de Lyon, Department of Pathology
Eliane Mery-Lamarche: IUCT-Oncopole
Justine Allard: Université Libre de Bruxelles
Egor Zindy: Université Libre de Bruxelles
Christine Decaestecker: Université Libre de Bruxelles
Isabelle Salmon: Université Libre de Bruxelles
David Perol: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Xavi Dolcet: Universidad de Lleida
Isabelle Ray-Coquard: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Cédric Blanpain: Université Libre de Bruxelles
Agnès Bernet: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Patrick Mehlen: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard

Nature, 2023, vol. 620, issue 7973, 409-416

Abstract: Abstract Netrin-1 is upregulated in cancers as a protumoural mechanism1. Here we describe netrin-1 upregulation in a majority of human endometrial carcinomas (ECs) and demonstrate that netrin-1 blockade, using an anti-netrin-1 antibody (NP137), is effective in reduction of tumour progression in an EC mouse model. We next examined the efficacy of NP137, as a first-in-class single agent, in a Phase I trial comprising 14 patients with advanced EC. As best response we observed 8 stable disease (8 out of 14, 57.1%) and 1 objective response as RECIST v.1.1 (partial response, 1 out of 14 (7.1%), 51.16% reduction in target lesions at 6 weeks and up to 54.65% reduction during the following 6 months). To evaluate the NP137 mechanism of action, mouse tumour gene profiling was performed, and we observed, in addition to cell death induction, that NP137 inhibited epithelial-to-mesenchymal transition (EMT). By performing bulk RNA sequencing (RNA-seq), spatial transcriptomics and single-cell RNA-seq on paired pre- and on-treatment biopsies from patients with EC from the NP137 trial, we noted a net reduction in tumour EMT. This was associated with changes in immune infiltrate and increased interactions between cancer cells and the tumour microenvironment. Given the importance of EMT in resistance to current standards of care2, we show in the EC mouse model that a combination of NP137 with carboplatin-paclitaxel outperformed carboplatin-paclitaxel alone. Our results identify netrin-1 blockade as a clinical strategy triggering both tumour debulking and EMT inhibition, thus potentially alleviating resistance to standard treatments.

Date: 2023
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DOI: 10.1038/s41586-023-06367-z

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