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Oncosuppressive miRNAs loaded in lipid nanoparticles potentiate targeted therapies in BRAF-mutant melanoma by inhibiting core escape pathways of resistance
BRAF-mutated melanoma relapsing after targeted therapies is an aggressive disease with unmet clinical need. Hence the need to identify novel combination therapies able to overcome drug resistance. miRNAs have emerged as orchestrators of non-genetic mechanisms adopted by melanoma cells to challenge t...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9684877/ https://www.ncbi.nlm.nih.gov/pubmed/36418472 http://dx.doi.org/10.1038/s41388-022-02547-9 |
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author | Fattore, Luigi Cafaro, Giordana Di Martile, Marta Campani, Virginia Sacconi, Andrea Liguoro, Domenico Marra, Emanuele Bruschini, Sara Stoppoloni, Daniela Cirombella, Roberto De Nicola, Francesca Pallocca, Matteo Ruggiero, Ciro F. Castaldo, Vittorio Catizone, Angiolina Del Bufalo, Donatella Viglietto, Giuseppe Vecchione, Andrea Blandino, Giovanni Aurisicchio, Luigi Fanciulli, Maurizio Ascierto, Paolo A. De Rosa, Giuseppe Mancini, Rita Ciliberto, Gennaro |
author_facet | Fattore, Luigi Cafaro, Giordana Di Martile, Marta Campani, Virginia Sacconi, Andrea Liguoro, Domenico Marra, Emanuele Bruschini, Sara Stoppoloni, Daniela Cirombella, Roberto De Nicola, Francesca Pallocca, Matteo Ruggiero, Ciro F. Castaldo, Vittorio Catizone, Angiolina Del Bufalo, Donatella Viglietto, Giuseppe Vecchione, Andrea Blandino, Giovanni Aurisicchio, Luigi Fanciulli, Maurizio Ascierto, Paolo A. De Rosa, Giuseppe Mancini, Rita Ciliberto, Gennaro |
author_sort | Fattore, Luigi |
collection | PubMed |
description | BRAF-mutated melanoma relapsing after targeted therapies is an aggressive disease with unmet clinical need. Hence the need to identify novel combination therapies able to overcome drug resistance. miRNAs have emerged as orchestrators of non-genetic mechanisms adopted by melanoma cells to challenge therapies. In this context we previously identified a subset of oncosuppressor miRNAs downregulated in drug-resistant melanomas. Here we demonstrate that lipid nanoparticles co-encapsulating two of them, miR-199-5p and miR-204-5p, inhibit tumor growth both in vitro and in vivo in combination with target therapy and block the development of drug resistance. Mechanistically they act by directly reducing melanoma cell growth and also indirectly by hampering the recruitment and reprogramming of pro-tumoral macrophages. Molecularly, we demonstrate that the effects on macrophages are mediated by the dysregulation of a newly identified miR-204-5p-miR-199b-5p/CCL5 axis. Finally, we unveiled that M2 macrophages programs are molecular signatures of resistance and predict response to therapy in patients. Overall, these findings have strong translational implications to propose new combination therapies making use of RNA therapeutics for metastatic melanoma patients. |
format | Online Article Text |
id | pubmed-9684877 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-96848772022-11-28 Oncosuppressive miRNAs loaded in lipid nanoparticles potentiate targeted therapies in BRAF-mutant melanoma by inhibiting core escape pathways of resistance Fattore, Luigi Cafaro, Giordana Di Martile, Marta Campani, Virginia Sacconi, Andrea Liguoro, Domenico Marra, Emanuele Bruschini, Sara Stoppoloni, Daniela Cirombella, Roberto De Nicola, Francesca Pallocca, Matteo Ruggiero, Ciro F. Castaldo, Vittorio Catizone, Angiolina Del Bufalo, Donatella Viglietto, Giuseppe Vecchione, Andrea Blandino, Giovanni Aurisicchio, Luigi Fanciulli, Maurizio Ascierto, Paolo A. De Rosa, Giuseppe Mancini, Rita Ciliberto, Gennaro Oncogene Article BRAF-mutated melanoma relapsing after targeted therapies is an aggressive disease with unmet clinical need. Hence the need to identify novel combination therapies able to overcome drug resistance. miRNAs have emerged as orchestrators of non-genetic mechanisms adopted by melanoma cells to challenge therapies. In this context we previously identified a subset of oncosuppressor miRNAs downregulated in drug-resistant melanomas. Here we demonstrate that lipid nanoparticles co-encapsulating two of them, miR-199-5p and miR-204-5p, inhibit tumor growth both in vitro and in vivo in combination with target therapy and block the development of drug resistance. Mechanistically they act by directly reducing melanoma cell growth and also indirectly by hampering the recruitment and reprogramming of pro-tumoral macrophages. Molecularly, we demonstrate that the effects on macrophages are mediated by the dysregulation of a newly identified miR-204-5p-miR-199b-5p/CCL5 axis. Finally, we unveiled that M2 macrophages programs are molecular signatures of resistance and predict response to therapy in patients. Overall, these findings have strong translational implications to propose new combination therapies making use of RNA therapeutics for metastatic melanoma patients. Nature Publishing Group UK 2022-11-23 2023 /pmc/articles/PMC9684877/ /pubmed/36418472 http://dx.doi.org/10.1038/s41388-022-02547-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Fattore, Luigi Cafaro, Giordana Di Martile, Marta Campani, Virginia Sacconi, Andrea Liguoro, Domenico Marra, Emanuele Bruschini, Sara Stoppoloni, Daniela Cirombella, Roberto De Nicola, Francesca Pallocca, Matteo Ruggiero, Ciro F. Castaldo, Vittorio Catizone, Angiolina Del Bufalo, Donatella Viglietto, Giuseppe Vecchione, Andrea Blandino, Giovanni Aurisicchio, Luigi Fanciulli, Maurizio Ascierto, Paolo A. De Rosa, Giuseppe Mancini, Rita Ciliberto, Gennaro Oncosuppressive miRNAs loaded in lipid nanoparticles potentiate targeted therapies in BRAF-mutant melanoma by inhibiting core escape pathways of resistance |
title | Oncosuppressive miRNAs loaded in lipid nanoparticles potentiate targeted therapies in BRAF-mutant melanoma by inhibiting core escape pathways of resistance |
title_full | Oncosuppressive miRNAs loaded in lipid nanoparticles potentiate targeted therapies in BRAF-mutant melanoma by inhibiting core escape pathways of resistance |
title_fullStr | Oncosuppressive miRNAs loaded in lipid nanoparticles potentiate targeted therapies in BRAF-mutant melanoma by inhibiting core escape pathways of resistance |
title_full_unstemmed | Oncosuppressive miRNAs loaded in lipid nanoparticles potentiate targeted therapies in BRAF-mutant melanoma by inhibiting core escape pathways of resistance |
title_short | Oncosuppressive miRNAs loaded in lipid nanoparticles potentiate targeted therapies in BRAF-mutant melanoma by inhibiting core escape pathways of resistance |
title_sort | oncosuppressive mirnas loaded in lipid nanoparticles potentiate targeted therapies in braf-mutant melanoma by inhibiting core escape pathways of resistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9684877/ https://www.ncbi.nlm.nih.gov/pubmed/36418472 http://dx.doi.org/10.1038/s41388-022-02547-9 |
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