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<p>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.</p><p></p>

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Ex.50.T aptamer impairs tumor–stroma cross-talk in breast cancer by targeting gremlin-1

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月11日

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  • Cristina Quintavalle,
  • Francesco Ingenito,
  • Giuseppina Roscigno,
  • Birlipta Pattanayak,
  • Carla Lucia Esposito,
  • Alessandra Affinito,
  • Danilo Fiore,
  • Gianluca Petrillo,
  • Silvia Nuzzo,
  • Bartolomeo Della Ventura,
  • Federica D’Aria,
  • Concetta Giancola,
  • Stefania Mitola,
  • Elisabetta Grillo,
  • Marinella Pirozzi,
  • Greta Donati,
  • Francesco Saverio Di Leva,
  • Luciana Marinelli,
  • Zoran Minic,
  • Francesca De Micco,
  • Guglielmo Thomas,
  • Maxim V. Berezovski,
  • Gerolama Condorelli

摘要

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.