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

四川生理科学杂志 2023年第8期45卷 1427-1427页

作者： Philippe A Cassier Centre Léon Bérard Departement de Recherche Clinique Centre de recherche en cancérologie de Lyon INSERM U1052-CNRS UMR5286 Université de Lyon Université Claude Bernard Lyon1 Centre Léon Bérard Lyon France Basic Medical Sciences Department Oncological Pathology Group Institut de Recerca Biomèdica de Lleida Universidad de Lleida Lleida Spain Apoptosis Cancer and Development Laboratory – Equipe labellisée ‘La Ligue’ LabEx DEVweCAN Institut PLAsCAN Centre de Recherche en Cancérologie de Lyon INSERM U1052-CNRS UMR5286 Université de Lyon Université Claude Bernard Lyon1 Centre Léon Bérard Lyon France netris pharma Lyon France Laboratory of Stem Cells and Cancer WEL Research Institute Université Libre de Bruxelles Brussels Belgium Centre de Recherche en Cancérologie de Lyon INSERM U1052-CNRS UMR 5286 Centre Léon Bérard Claude Bernard Lyon 1 University Lyon France Institut Claudius Regaud IUCT-Oncopole Toulouse France CRCL Core facilities Centre de Recherche en Cancérologie de Lyon (CRCL) INSERM U1052-CNRS UMR5286 Université de Lyon Université Claude Bernard Lyon1 Centre Léon Bérard Lyon France Hospices Civils de Lyon Department of Pathology Lyon France Department of Pathology IUCT-Oncopole Toulouse France DIAPath Center for microscopy and molecular Imaging Université Libre de Bruxelles Gosselies Belgium Laboratory of Image Synthesis and Analysis Ecole Polytechnique-Université libre de Bruxelles Brussels Belgium Departement of Pathology Erasme University Hospital Université Libre de Bruxelles Brussels Belgium Centre Universitaire Inter Régional d’Expertise en Anatomie pathologique Hospitalière (CurePath) Jumet Belgium

Netrin-1 is upregulated in cancers as a protumoural *** 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 *** next examined the efficacy of NP137,as a first-in-class single agent,in a Phase I trial comprising 14 patients with advanced *** 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 *** was associated with changes in immune infiltrate and increased interactions between cancer cells and the tumour *** 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 *** results identify netrin-1 blockade as a clinical strategy triggering both tumour debulking and EMT inhibition,thus potentially alleviating resistance to standard treatments.

关键词： tumour inhibited EMT

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