Exosomes modified with anti-MEK1 siRNA lead to an effective silencing of triple negative breast cancer cells

• Published in: Biomaterials advances 2023-11, Vol.154, p.1-13, Article 213643
• Main Authors: Ferreira, Débora Carina Gonçalves Abreu, Pereira, Cátia Sofia Santos, Costa, Marta, Afonso, Julieta Alexandra Pereira, Yang, Sujuan, Hensel, Janine, McAndrews, Kathleen M., Longatto, Adhemar, Fernandes, Rui, Melo, Joana B., Baltazar, Fátima, Moreira, João N., Kalluri, Raghu, Rodrigues, L. R.
• Format: Article
• Language: English
• Subjects: MAPK/ERK cascade; MEK1; siRNA; TNBC
• ISSN: 2772-9508; 2772-9508
• DOI: 10.1016/j.bioadv.2023.213643

Available online 28 September 2023 Triple negative breast cancer (TNBC) is a highly heterogenous disease not sensitive to endocrine or HER2 therapy and standardized treatment regimens are still missing. Therefore, development of novel TNBC treatment approaches is of utmost relevance. Herein, the potential of MAPK/ERK downregulation by RNAi-based therapeutics in a panel of mesenchymal stem-like TNBC cell lines was uncovered. Our data revealed that suppression of one of the central nodes of this signaling pathway, MEK1, affects proliferation, migration, and invasion of TNBC cells, that may be explained by the reversion of the epithelial-mesenchymal transition phenotype, which is facilitated by the MMP-2/MMP-9 downregulation. Moreover, an exosome-based system was successfully generated for the siRNA loading (iExoMEK1). Our data suggested absence of modification of the physical properties and general integrity of the iExoMEK1 comparatively to the unmodified counterparts. Such exosome-mediated downregulation of MEK1 led to a tumor regression accompanied by a decrease of angiogenesis using the chick chorioallantoic-membrane model. Our results highlight the potential of the targeting of MAPK/ERK cascade as a promising therapeutic approach against TNBC. This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/ BIO/04469/2020 unit. CAM and immunohistochemistry experiments have been funded by ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI - Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122); by National funds, through the Foundation for Science and Technology (FCT) - project UIDB/50026/ 2020 and UIDP/50026/2020 and by the project NORTE-01-0145- FEDER-000039, supported by Norte Portugal Regional Operational Program (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Débora Ferreira is recipient of a fellowship supported by a doctoral advanced training (call NORTE-69-2015-15) funded by the European Social Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. Débora Ferreira also acknowledges “Liga Portuguesa contra o cancro - Núcleo Regional do Norte (LPCC-NRN)” for her fellowship. The authors thank Diana Vilas Boas (CEB/University of Minho) for confocal microscopy technical support. Cátia Santos-Pereira acknowledges the PhD fellowship PD/BD/128032/2016 funde