期刊
CANCER GENE THERAPY
卷 29, 期 7, 页码 1056-1069出版社
SPRINGERNATURE
DOI: 10.1038/s41417-021-00411-8
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资金
- Instituto de Salud Carlos III [PI16/00107, PI19/00245, RD16/0011/0004]
- European Regional Development Fund (FEDER una manera de hacer Europa)
- Conselleria de Sanitat Universal i Salut Publica [ACIF/2018/259, ACIF/2017/318]
- European Union through the Operational Program of FEDER of the Valencian Community 2014-2020
This study investigates the involvement of small extracellular vesicles (SEVs) in functional Notch signaling and finds that SEVs in breast cancer cells can regulate Notch signal transduction, leading to increased invasiveness and proliferation of breast cancer cells.
Aberrant Notch signaling is implicated in breast cancer progression, and recent studies have demonstrated links between the Notch pathway components Notch1 and Notch1 intracellular domain (N1ICD) with poor clinical outcomes. Growing evidence suggests that Notch signaling can be regulated by small extracellular vesicles (SEVs). Here, we used breast cancer cell models to examine whether SEVs are involved in functional Notch signaling. We found that Notch components are packaged into MDA-MB-231- and MCF-7-derived SEVs, although higher levels of N1ICD were detected in SEVs from the more aggressive MDA-MB-231 cell line than from poorly invasive MCF-7 cells. SEV-Notch components were functional, as SEVs cargo from MDA-MB-231 cells induced the expression of Notch target genes in MCF-7 cells and triggered a more invasive and proliferative phenotype concomitant with the acquisition of mesenchymal features. Neutralization of the N1ICD cargo in MDA-MB-231-derived SEVs significantly reduced their potential to enhance the aggressiveness of MCF-7 cells in vitro and in a xenograft model. Overall, our results indicate that a SEV-mediated non-classical pathway of Notch signal transduction in breast cancer models bypasses the need for classical ligand-receptor interactions, which may have important implications in cancer.
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