دورية أكاديمية
CRISPR screens identify tumor‐promoting genes conferring melanoma cell plasticity and resistance
| العنوان: | CRISPR screens identify tumor‐promoting genes conferring melanoma cell plasticity and resistance |
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| المؤلفون: | Arthur Gautron, Laura Bachelot, Marc Aubry, Delphine Leclerc, Anaïs M Quéméner, Sébastien Corre, Florian Rambow, Anaïs Paris, Nina Tardif, Héloïse M Leclair, Oskar Marin‐Bejar, Cédric Coulouarn, Jean‐Christophe Marine, Marie‐Dominique Galibert, David Gilot |
| المصدر: | EMBO Molecular Medicine, Vol 13, Iss 5, Pp n/a-n/a (2021) |
| بيانات النشر: | Springer Nature, 2021. |
| سنة النشر: | 2021 |
| المجموعة: | LCC:Medicine (General) LCC:Genetics |
| مصطلحات موضوعية: | Aryl hydrocarbon Receptor, CRISPR‐SAM, melanoma, SMAD3, targeted therapy resistance, Medicine (General), R5-920, Genetics, QH426-470 |
| الوصف: | Abstract Most genetic alterations that drive melanoma development and resistance to targeted therapy have been uncovered. In contrast, and despite their increasingly recognized contribution, little is known about the non‐genetic mechanisms that drive these processes. Here, we performed in vivo gain‐of‐function CRISPR screens and identified SMAD3, BIRC3, and SLC9A5 as key actors of BRAFi resistance. We show that their expression levels increase during acquisition of BRAFi resistance and remain high in persister cells and during relapse. The upregulation of the SMAD3 transcriptional activity (SMAD3‐signature) promotes a mesenchymal‐like phenotype and BRAFi resistance by acting as an upstream transcriptional regulator of potent BRAFi‐resistance genes such as EGFR and AXL. This SMAD3‐signature predicts resistance to both current melanoma therapies in different cohorts. Critically, chemical inhibition of SMAD3 may constitute amenable target for melanoma since it efficiently abrogates persister cells survival. Interestingly, decrease of SMAD3 activity can also be reached by inhibiting the Aryl hydrocarbon Receptor (AhR), another druggable transcription factor governing SMAD3 expression level. Our work highlights novel drug vulnerabilities that can be exploited to develop long‐lasting antimelanoma therapies. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1757-4684 1757-4676 20201346 |
| Relation: | https://doaj.org/toc/1757-4676; https://doaj.org/toc/1757-4684 |
| DOI: | 10.15252/emmm.202013466 |
| URL الوصول: | https://doaj.org/article/aca2254b33d042efb8994b39d40584e3 |
| رقم الأكسشن: | edsdoj.2254b33d042efb8994b39d40584e3 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 17574684 17574676 20201346 |
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| DOI: | 10.15252/emmm.202013466 |