CRISPR screens identify tumor‐promoting genes conferring melanoma cell plasticity and resistance
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‐...
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Online Access: | https://doi.org/10.15252/emmm.202013466 |
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doaj-aca2254b33d042efb8994b39d40584e32021-08-02T21:23:19ZengWileyEMBO Molecular Medicine1757-46761757-46842021-05-01135n/an/a10.15252/emmm.202013466CRISPR screens identify tumor‐promoting genes conferring melanoma cell plasticity and resistanceArthur Gautron0Laura Bachelot1Marc Aubry2Delphine Leclerc3Anaïs M Quéméner4Sébastien Corre5Florian Rambow6Anaïs Paris7Nina Tardif8Héloïse M Leclair9Oskar Marin‐Bejar10Cédric Coulouarn11Jean‐Christophe Marine12Marie‐Dominique Galibert13David Gilot14CNRS IGDR (Institut de génétique et développement de Rennes)‐UMR 6290 Univ Rennes Rennes FranceCNRS IGDR (Institut de génétique et développement de Rennes)‐UMR 6290 Univ Rennes Rennes FranceCNRS IGDR (Institut de génétique et développement de Rennes)‐UMR 6290 Univ Rennes Rennes FranceINSERM U1242 Centre Eugène Marquis Rennes FranceCNRS IGDR (Institut de génétique et développement de Rennes)‐UMR 6290 Univ Rennes Rennes FranceCNRS IGDR (Institut de génétique et développement de Rennes)‐UMR 6290 Univ Rennes Rennes FranceDepartment of Oncology KU Leuven Leuven BelgiumCNRS IGDR (Institut de génétique et développement de Rennes)‐UMR 6290 Univ Rennes Rennes FranceCNRS IGDR (Institut de génétique et développement de Rennes)‐UMR 6290 Univ Rennes Rennes FranceCNRS IGDR (Institut de génétique et développement de Rennes)‐UMR 6290 Univ Rennes Rennes FranceDepartment of Oncology KU Leuven Leuven BelgiumINSERM U1242 Centre Eugène Marquis Rennes FranceDepartment of Oncology KU Leuven Leuven BelgiumCNRS IGDR (Institut de génétique et développement de Rennes)‐UMR 6290 Univ Rennes Rennes FranceCNRS IGDR (Institut de génétique et développement de Rennes)‐UMR 6290 Univ Rennes Rennes FranceAbstract 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.https://doi.org/10.15252/emmm.202013466Aryl hydrocarbon ReceptorCRISPR‐SAMmelanomaSMAD3targeted therapy resistance |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 CRISPR screens identify tumor‐promoting genes conferring melanoma cell plasticity and resistance EMBO Molecular Medicine Aryl hydrocarbon Receptor CRISPR‐SAM melanoma SMAD3 targeted therapy resistance |
author_facet |
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 |
author_sort |
Arthur Gautron |
title |
CRISPR screens identify tumor‐promoting genes conferring melanoma cell plasticity and resistance |
title_short |
CRISPR screens identify tumor‐promoting genes conferring melanoma cell plasticity and resistance |
title_full |
CRISPR screens identify tumor‐promoting genes conferring melanoma cell plasticity and resistance |
title_fullStr |
CRISPR screens identify tumor‐promoting genes conferring melanoma cell plasticity and resistance |
title_full_unstemmed |
CRISPR screens identify tumor‐promoting genes conferring melanoma cell plasticity and resistance |
title_sort |
crispr screens identify tumor‐promoting genes conferring melanoma cell plasticity and resistance |
publisher |
Wiley |
series |
EMBO Molecular Medicine |
issn |
1757-4676 1757-4684 |
publishDate |
2021-05-01 |
description |
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. |
topic |
Aryl hydrocarbon Receptor CRISPR‐SAM melanoma SMAD3 targeted therapy resistance |
url |
https://doi.org/10.15252/emmm.202013466 |
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