Blockade of the pro‐fibrotic reaction mediated by the miR‐143/‐145 cluster enhances the responses to targeted therapy in melanoma
Abstract Lineage dedifferentiation toward a mesenchymal‐like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and acquired resistance to targeted therapy in melanoma. Here, we show that the anti‐fibrotic drug nintedanib is active to normalize the fibrous ECM net...
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2022-03-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202115295 |
| _version_ | 1797288840376877056 |
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| author | Serena Diazzi Alberto Baeri Julien Fassy Margaux Lecacheur Oskar Marin‐Bejar Christophe A Girard Lauren Lefevre Caroline Lacoux Marie Irondelle Carine Mounier Marin Truchi Marie Couralet Mickael Ohanna Alexandrine Carminati Ilona Berestjuk Frederic Larbret David Gilot Georges Vassaux Jean‐Christophe Marine Marcel Deckert Bernard Mari Sophie Tartare‐Deckert |
| author_facet | Serena Diazzi Alberto Baeri Julien Fassy Margaux Lecacheur Oskar Marin‐Bejar Christophe A Girard Lauren Lefevre Caroline Lacoux Marie Irondelle Carine Mounier Marin Truchi Marie Couralet Mickael Ohanna Alexandrine Carminati Ilona Berestjuk Frederic Larbret David Gilot Georges Vassaux Jean‐Christophe Marine Marcel Deckert Bernard Mari Sophie Tartare‐Deckert |
| author_sort | Serena Diazzi |
| collection | DOAJ |
| description | Abstract Lineage dedifferentiation toward a mesenchymal‐like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and acquired resistance to targeted therapy in melanoma. Here, we show that the anti‐fibrotic drug nintedanib is active to normalize the fibrous ECM network, enhance the efficacy of MAPK‐targeted therapy, and delay tumor relapse in a preclinical model of melanoma. Acquisition of this resistant phenotype and its reversion by nintedanib pointed to miR‐143/‐145 pro‐fibrotic cluster as a driver of this mesenchymal‐like phenotype. Upregulation of the miR‐143/‐145 cluster under BRAFi/MAPKi therapy was observed in melanoma cells in vitro and in vivo and was associated with an invasive/undifferentiated profile. The 2 mature miRNAs generated from this cluster, miR‐143‐3p and miR‐145‐5p, collaborated to mediate transition toward a drug‐resistant undifferentiated mesenchymal‐like state by targeting Fascin actin‐bundling protein 1 (FSCN1), modulating the dynamic crosstalk between the actin cytoskeleton and the ECM through the regulation of focal adhesion dynamics and mechanotransduction pathways. Our study brings insights into a novel miRNA‐mediated regulatory network that contributes to non‐genetic adaptive drug resistance and provides proof of principle that preventing MAPKi‐induced pro‐fibrotic stromal response is a viable therapeutic opportunity for patients on targeted therapy. |
| first_indexed | 2024-03-07T18:55:23Z |
| format | Article |
| id | doaj.art-671e1303a548439c811055b9bfe4b17f |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T18:55:23Z |
| publishDate | 2022-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-671e1303a548439c811055b9bfe4b17f2024-03-02T00:27:55ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-03-01143n/an/a10.15252/emmm.202115295Blockade of the pro‐fibrotic reaction mediated by the miR‐143/‐145 cluster enhances the responses to targeted therapy in melanomaSerena Diazzi0Alberto Baeri1Julien Fassy2Margaux Lecacheur3Oskar Marin‐Bejar4Christophe A Girard5Lauren Lefevre6Caroline Lacoux7Marie Irondelle8Carine Mounier9Marin Truchi10Marie Couralet11Mickael Ohanna12Alexandrine Carminati13Ilona Berestjuk14Frederic Larbret15David Gilot16Georges Vassaux17Jean‐Christophe Marine18Marcel Deckert19Bernard Mari20Sophie Tartare‐Deckert21Université Côte d'Azur INSERM C3M Nice FranceUniversité Côte d'Azur CNRS Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) Sophia Antipolis FranceUniversité Côte d'Azur CNRS Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) Sophia Antipolis FranceUniversité Côte d'Azur INSERM C3M Nice FranceLaboratory For Molecular Cancer Biology VIB Center for Cancer Biology VIB Leuven BelgiumUniversité Côte d'Azur INSERM C3M Nice FranceUniversité Côte d'Azur INSERM C3M Nice FranceUniversité Côte d'Azur CNRS Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) Sophia Antipolis FranceUniversité Côte d'Azur INSERM C3M Nice FranceUniversité Côte d'Azur CNRS Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) Sophia Antipolis FranceUniversité Côte d'Azur CNRS Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) Sophia Antipolis FranceUniversité Côte d'Azur CNRS Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) Sophia Antipolis FranceUniversité Côte d'Azur INSERM C3M Nice FranceUniversité Côte d'Azur INSERM C3M Nice FranceUniversité Côte d'Azur INSERM C3M Nice FranceUniversité Côte d'Azur INSERM C3M Nice FranceINSERM U1242 University of Rennes Rennes FranceUniversité Côte d'Azur CNRS Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) Sophia Antipolis FranceLaboratory For Molecular Cancer Biology VIB Center for Cancer Biology VIB Leuven BelgiumUniversité Côte d'Azur INSERM C3M Nice FranceUniversité Côte d'Azur CNRS Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) Sophia Antipolis FranceUniversité Côte d'Azur INSERM C3M Nice FranceAbstract Lineage dedifferentiation toward a mesenchymal‐like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and acquired resistance to targeted therapy in melanoma. Here, we show that the anti‐fibrotic drug nintedanib is active to normalize the fibrous ECM network, enhance the efficacy of MAPK‐targeted therapy, and delay tumor relapse in a preclinical model of melanoma. Acquisition of this resistant phenotype and its reversion by nintedanib pointed to miR‐143/‐145 pro‐fibrotic cluster as a driver of this mesenchymal‐like phenotype. Upregulation of the miR‐143/‐145 cluster under BRAFi/MAPKi therapy was observed in melanoma cells in vitro and in vivo and was associated with an invasive/undifferentiated profile. The 2 mature miRNAs generated from this cluster, miR‐143‐3p and miR‐145‐5p, collaborated to mediate transition toward a drug‐resistant undifferentiated mesenchymal‐like state by targeting Fascin actin‐bundling protein 1 (FSCN1), modulating the dynamic crosstalk between the actin cytoskeleton and the ECM through the regulation of focal adhesion dynamics and mechanotransduction pathways. Our study brings insights into a novel miRNA‐mediated regulatory network that contributes to non‐genetic adaptive drug resistance and provides proof of principle that preventing MAPKi‐induced pro‐fibrotic stromal response is a viable therapeutic opportunity for patients on targeted therapy.https://doi.org/10.15252/emmm.202115295fibrosisMAPK inhibitorsmelanomamicroRNAnintedanib |
| spellingShingle | Serena Diazzi Alberto Baeri Julien Fassy Margaux Lecacheur Oskar Marin‐Bejar Christophe A Girard Lauren Lefevre Caroline Lacoux Marie Irondelle Carine Mounier Marin Truchi Marie Couralet Mickael Ohanna Alexandrine Carminati Ilona Berestjuk Frederic Larbret David Gilot Georges Vassaux Jean‐Christophe Marine Marcel Deckert Bernard Mari Sophie Tartare‐Deckert Blockade of the pro‐fibrotic reaction mediated by the miR‐143/‐145 cluster enhances the responses to targeted therapy in melanoma EMBO Molecular Medicine fibrosis MAPK inhibitors melanoma microRNA nintedanib |
| title | Blockade of the pro‐fibrotic reaction mediated by the miR‐143/‐145 cluster enhances the responses to targeted therapy in melanoma |
| title_full | Blockade of the pro‐fibrotic reaction mediated by the miR‐143/‐145 cluster enhances the responses to targeted therapy in melanoma |
| title_fullStr | Blockade of the pro‐fibrotic reaction mediated by the miR‐143/‐145 cluster enhances the responses to targeted therapy in melanoma |
| title_full_unstemmed | Blockade of the pro‐fibrotic reaction mediated by the miR‐143/‐145 cluster enhances the responses to targeted therapy in melanoma |
| title_short | Blockade of the pro‐fibrotic reaction mediated by the miR‐143/‐145 cluster enhances the responses to targeted therapy in melanoma |
| title_sort | blockade of the pro fibrotic reaction mediated by the mir 143 145 cluster enhances the responses to targeted therapy in melanoma |
| topic | fibrosis MAPK inhibitors melanoma microRNA nintedanib |
| url | https://doi.org/10.15252/emmm.202115295 |
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