Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer
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 m...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universitat de Lleida (UdL) |
| Repositorio: | Repositori Obert UdL |
| OAI Identifier: | oai:repositori.udl.cat:10459.1/464276 |
| Acceso en línea: | https://doi.org/10.1038/s41586-023-06367-z https://hdl.handle.net/10459.1/464276 |
| Access Level: | acceso abierto |
| Palabra clave: | Netrin-1 Antagonists & inhibitors |
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Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancerCassier, Philippe A.Navaridas Fernández de Bobadilla, RaúlBellina, MelanieRama, NicolasDucarouge, BenjaminHernandez-Vargas, HectorDelord, Jean-PierreLengrand, JustineParadisi, AndreaFattet, LaurentGarin, GwenaëleGheit, HananeDalban, CecilePastushenko, IevgeniaNeves, DavidJelin, RemyGadot, NicolasBraissand, NicolasLéon, SophieDegletagne, CyrilMatias-Guiu, XavierDevouassoux-Shisheboran, MojganMery-Lamarche, ElianeAllard, JustineZindy, EgorDecaestecker, ChristineSalmon, IsabellePerol, DavidDolcet Roca, XavierRay-Coquard, IsabelleBlanpain, CédricBernet, AgnèsMehlen, PatrickNetrin-1Antagonists & inhibitorsNetrin-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.Nature Research2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.1038/s41586-023-06367-zhttps://hdl.handle.net/10459.1/464276reponame:Repositori Obert UdL instname:Universitat de Lleida (UdL)InglésReproducció del document publicat a: https://doi.org/10.1038/s41586-023-06367-zNature, 2023, vol. 620, p. 409–416cc-by (c) the Authors, 2023Attribution 4.0 Internationalinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/oai:repositori.udl.cat:10459.1/4642762026-06-24T12:42:17Z |
| dc.title.none.fl_str_mv |
Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer |
| title |
Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer |
| spellingShingle |
Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer Cassier, Philippe A. Netrin-1 Antagonists & inhibitors |
| title_short |
Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer |
| title_full |
Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer |
| title_fullStr |
Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer |
| title_full_unstemmed |
Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer |
| title_sort |
Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer |
| dc.creator.none.fl_str_mv |
Cassier, Philippe A. Navaridas Fernández de Bobadilla, Raúl Bellina, Melanie Rama, Nicolas Ducarouge, Benjamin Hernandez-Vargas, Hector Delord, Jean-Pierre Lengrand, Justine Paradisi, Andrea Fattet, Laurent Garin, Gwenaële Gheit, Hanane Dalban, Cecile Pastushenko, Ievgenia Neves, David Jelin, Remy Gadot, Nicolas Braissand, Nicolas Léon, Sophie Degletagne, Cyril Matias-Guiu, Xavier Devouassoux-Shisheboran, Mojgan Mery-Lamarche, Eliane Allard, Justine Zindy, Egor Decaestecker, Christine Salmon, Isabelle Perol, David Dolcet Roca, Xavier Ray-Coquard, Isabelle Blanpain, Cédric Bernet, Agnès Mehlen, Patrick |
| author |
Cassier, Philippe A. |
| author_facet |
Cassier, Philippe A. Navaridas Fernández de Bobadilla, Raúl Bellina, Melanie Rama, Nicolas Ducarouge, Benjamin Hernandez-Vargas, Hector Delord, Jean-Pierre Lengrand, Justine Paradisi, Andrea Fattet, Laurent Garin, Gwenaële Gheit, Hanane Dalban, Cecile Pastushenko, Ievgenia Neves, David Jelin, Remy Gadot, Nicolas Braissand, Nicolas Léon, Sophie Degletagne, Cyril Matias-Guiu, Xavier Devouassoux-Shisheboran, Mojgan Mery-Lamarche, Eliane Allard, Justine Zindy, Egor Decaestecker, Christine Salmon, Isabelle Perol, David Dolcet Roca, Xavier Ray-Coquard, Isabelle Blanpain, Cédric Bernet, Agnès Mehlen, Patrick |
| author_role |
author |
| author2 |
Navaridas Fernández de Bobadilla, Raúl Bellina, Melanie Rama, Nicolas Ducarouge, Benjamin Hernandez-Vargas, Hector Delord, Jean-Pierre Lengrand, Justine Paradisi, Andrea Fattet, Laurent Garin, Gwenaële Gheit, Hanane Dalban, Cecile Pastushenko, Ievgenia Neves, David Jelin, Remy Gadot, Nicolas Braissand, Nicolas Léon, Sophie Degletagne, Cyril Matias-Guiu, Xavier Devouassoux-Shisheboran, Mojgan Mery-Lamarche, Eliane Allard, Justine Zindy, Egor Decaestecker, Christine Salmon, Isabelle Perol, David Dolcet Roca, Xavier Ray-Coquard, Isabelle Blanpain, Cédric Bernet, Agnès Mehlen, Patrick |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Netrin-1 Antagonists & inhibitors |
| topic |
Netrin-1 Antagonists & inhibitors |
| description |
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. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
| dc.identifier.none.fl_str_mv |
https://doi.org/10.1038/s41586-023-06367-z https://hdl.handle.net/10459.1/464276 |
| url |
https://doi.org/10.1038/s41586-023-06367-z https://hdl.handle.net/10459.1/464276 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Reproducció del document publicat a: https://doi.org/10.1038/s41586-023-06367-z Nature, 2023, vol. 620, p. 409–416 |
| dc.rights.none.fl_str_mv |
cc-by (c) the Authors, 2023 Attribution 4.0 International info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/4.0/ |
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cc-by (c) the Authors, 2023 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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Nature Research |
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Nature Research |
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reponame:Repositori Obert UdL instname:Universitat de Lleida (UdL) |
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Universitat de Lleida (UdL) |
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