Related Experiment Video
Updated: Oct 6, 2025
A Preclinical Mouse Model of Osteosarcoma to Define the Extracellular Vesicle-mediated Communication Between Tumor and Mesenchymal Stem Cells
Published on: May 6, 2018
Non-classical Notch signaling by MDA-MB-231 breast cancer cell-derived small extracellular vesicles promotes
Hernán González-King1, Sandra Tejedor1, María Ciria1
1Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria la Fe, Valencia, Spain.
Abstract:
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.
Insights
Small extracellular vesicles (SEVs) transfer functional Notch signaling components, including Notch1 intracellular domain (N1ICD), between breast cancer cells. This SEV-mediated pathway promotes cancer progression and invasiveness, offering new therapeutic targets.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Aberrant Notch signaling is linked to poor breast cancer outcomes.
- Small extracellular vesicles (SEVs) are increasingly recognized as regulators of cellular communication.
- Notch pathway components, Notch1 and its intracellular domain (N1ICD), are implicated in cancer progression.
Purpose of the Study:
- To investigate the role of SEVs in functional Notch signaling in breast cancer.
- To determine if Notch components are packaged into SEVs and if they are functional.
- To assess the impact of SEV-mediated Notch signaling on breast cancer aggressiveness.
Main Methods:
- Utilized breast cancer cell models (MDA-MB-231 and MCF-7).
- Analyzed Notch component packaging into SEVs.
- Assessed the functional impact of SEV-derived Notch components on recipient cells.
- Investigated the effect of N1ICD neutralization in SEVs.
Main Results:
- Notch components, including N1ICD, were detected in SEVs derived from breast cancer cells.
- SEVs from aggressive MDA-MB-231 cells transferred functional Notch signaling to less invasive MCF-7 cells.
- SEV-mediated Notch signaling promoted target gene expression, increased invasiveness, proliferation, and mesenchymal features.
- Neutralizing N1ICD in SEVs reduced their ability to enhance cancer cell aggressiveness.
Conclusions:
- SEVs mediate a non-classical pathway for Notch signal transduction in breast cancer.
- This SEV-driven pathway bypasses traditional ligand-receptor interactions.
- SEV-mediated Notch signaling contributes to breast cancer progression and invasiveness.
- Targeting SEV-mediated Notch signaling may offer novel therapeutic strategies for breast cancer.
Related Concept Videos
03:14Notch Signaling Pathway
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
02:30Metastasis
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...
01:35Cancer Cell Migration through Invadopodia
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...