Ex.50.T aptamer impairs tumor–stroma cross-talk in breast cancer by targeting gremlin-1
The tumor microenvironment profoundly influences tumor complexity, particularly in breast cancer, where cancer-associated fibroblasts play pivotal roles in tumor progression and therapy resistance. Extracellular vesicles are involved in mediating communication within the TME, specifically highlighting their role in promoting the transformation of normal fibroblasts into cancer-associated fibroblasts. Recently, we identified an RNA aptamer, namely ex.50.T, that binds with remarkable affinity to extracellular vesicles shed from triple-negative breast cancer cells. Here, through in vitro assays and computational analyses, we demonstrate that the binding of ex.50.T to extracellular vesicles and parental breast cancer cells is mediated by recognition of gremlin-1 (GREM1), a bone morphogenic protein antagonist implicated in breast cancer aggressiveness and metastasis. Functionally, we uncover the role of ex.50.T as an innovative therapeutic agent in the process of tumor microenvironment re-modeling, impeding GREM1 signaling, blocking triple-negative breast cancer extracellular vesicles internalization in recipient cells, and counteracting the transformation of normal fibroblasts into cancer-associated fibroblasts. Altogether, our findings highlight ex.50.T as a novel therapeutical avenue for breast cancer and potentially other GREM1-dependent malignancies, offering insights into disrupting TME dynamics and enhancing cancer treatment strategies.
Authors
- Cristina Quintavalle (ORCID: https://orcid.org/0000-0002-7432-9170)
- Marinella Pirozzi (ORCID: https://orcid.org/0000-0002-1714-2000)
- Elisabetta Grillo (ORCID: https://orcid.org/0000-0002-8403-0607)
- Luciana Marinelli (ORCID: https://orcid.org/0000-0002-4084-8044)
- Danilo Fiore (ORCID: https://orcid.org/0000-0003-3004-6862)
- Maxim V. Berezovski (ORCID: https://orcid.org/0000-0003-0514-599X)
- Carla Lucia Esposito (ORCID: https://orcid.org/0000-0003-0624-6821)
- Federica D’Aria (ORCID: https://orcid.org/0000-0001-5589-2841)
- F. Ingenito
- Bartolomeo Della Ventura (ORCID: https://orcid.org/0000-0003-2920-6187)
- Stefania Maria Filomena Mitola (ORCID: https://orcid.org/0000-0002-5557-738X)
- Alessandra Affinito (ORCID: https://orcid.org/0000-0002-3887-6513)
- Guglielmo Thomas (ORCID: https://orcid.org/0000-0003-1984-4732)
- Francesco Saverio Di Leva (ORCID: https://orcid.org/0000-0002-2294-0656)
- Birlipta Pattanayak
- Silvia Nuzzo (ORCID: https://orcid.org/0000-0002-6537-7867)
- Concetta Giancola (ORCID: https://orcid.org/0000-0002-0360-6062)
- Giuseppina Roscigno (ORCID: https://orcid.org/0000-0002-5359-6376)
- Greta Donati (ORCID: https://orcid.org/0000-0002-0311-1721)
- Francesca De Micco
- Zoran Minić (ORCID: https://orcid.org/0000-0003-2520-0239)
- Gianluca Petrillo (ORCID: https://orcid.org/0000-0003-0719-7072)
- Gerolama Condorelli (ORCID: https://orcid.org/0000-0003-0177-8829)
Institutions
- University of Ottawa (CA)
- Federico II University Hospital (IT)
- Clinica Mediterranea (IT)
- Etna Biotech (Italy) (IT)
- Institute for Experimental Endocrinology and Oncology (IT)
- University of Naples Federico II (IT)
- University of Brescia (IT)
Publication Details
- Journal
- Cell Death Discovery
- Published
- 2025-03-11
- DOI
- https://doi.org/10.1038/s41420-025-02363-6
- Citations
- 3
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 2.42