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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jun 02, 2023 |
| Title |
Netrin-1 blockade induces tumor growth inhibition and EMT reversion in endometrial cancer [scRNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Netrin-1 is up-regulated in a large fraction of human cancers as a pro-tumoralmechanism. Therefore, a phase I trial assessing netrin-1 blockade using an anti- netrin-1 monoclonal antibody (NP137) in patients with advanced solid cancer is ongoing. We analyzed here the potential implication of netrin-1 in endometrial carcinoma. We show that netrin-1 is up-regulated in the vast majority of human endometrial carcinomas, and demonstrate that NP137 treatment is effective in reducing tumor progression in preclinical mouse models of endometrial carcinoma. We report here a confirmed objective response in a patient with endometrial carcinoma (EC) treated in monotherapy with NP137. A 51.16% reduction of target lesions at 6 weeks and up to 54.65% reduction during the next 6 months of NP137 treatment was observed for a 74 years old woman. To evaluate the mechanism of action of the anti-netrin-1 mAb, we performed gene profiling of mouse PTENf/f endometrial tumors treated with NP137 and observed that, in addition to cell death induction, NP137 induced a reversion of the Epithelial-to-Mesenchymal Transition (EMT). Of interest, by analyzing 13 pre/post paired biopsies of the patients with endometrial carcinoma treated in the NP137 trial, we confirmed a significant reduction of EMT in tumors. We thus performed pre/post NP137 treatment biopsy- based single cell RNA sequencing in a patient with endometrial carcinoma, and showed a net decrease of neoplastic cells and a reversion of EMT markers in the remaining tumor cells, with associated change in the tumor microenvironment. Given the importance of EMT in resistance to the current standard of care including chemotherapy or immune-checkpoint inhibitors, we showed in a PTENf/f endometrial cancer mouse model that combining NP137 with carboplatin paclitaxel outperformed carboplatin paclitaxel alone. Our results thus identify for the first time, in preclinical models and in patients, netrin-1 blockade as a clinical strategy triggering both tumor debulking and reversion of EMT, thus potentially alleviating resistance to standard treatments.
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| Overall design |
Single cell RNAseq analysis of pre/upon biopsy of a patient with endometrial adenocarcinoma. 2 lung metastasis biopsies were collected : C1D1 (at inclusion) and C3D1 (after one month of treatment with NP137).
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| Contributor(s) |
Cassier PA, Navaridas R, Rama N, Ducarouge B, Delord J, Bellina M, Paradisi A, Garin G, Gheit H, Neves D, Jelin R, Gadot N, Léon S, Degletagne C, Devouassoux-Shisheboran M, Mery-Lamarche E, Perol D, Dolcet X, Ray-Coquard I, Bernet A, Mehlen P, Hernandez-Vargas H |
| Citation(s) |
37532934 |
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| Submission date |
Feb 21, 2023 |
| Last update date |
Aug 16, 2023 |
| Contact name |
Nicolas Rama |
| E-mail(s) |
nicolas.rama@lyon.unicancer.fr
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| Organization name |
CRCL
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| Street address |
28 rue Laennec
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| City |
LYON |
| ZIP/Postal code |
69890 |
| Country |
France |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (2) |
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| This SubSeries is part of SuperSeries: |
| GSE225691 |
Netrin-1 blockade induces tumor growth inhibition and EMT reversion in endometrial cancer. |
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| Relations |
| BioProject |
PRJNA937166 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE225689_RAW.tar |
169.4 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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