1. Osteosarcoma-Derived Extracellular Vesicles Induce Lung Fibroblast Reprogramming
- Author
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Alekhya Mazumdar, Joaquin Urdinez, Aleksandar Boro, Jessica Migliavacca, Matthias J.E. Arlt, Roman Muff, Bruno Fuchs, Jess Gerrit Snedeker, and Ana Gvozdenovic
- Subjects
osteosarcoma ,extracellular vesicles ,lung fibroblasts ,tumor microenvironment ,tumor-host interactions ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Tumor-secreted extracellular vesicles (EVs) have been identified as mediators of cancer–host intercellular communication and shown to support pre-metastatic niche formation by modulating stromal cells at future metastatic sites. While osteosarcoma, the most common primary malignant bone tumor in children and adolescents, has a high propensity for pulmonary metastases, the interaction of osteosarcoma cells with resident lung cells remains poorly understood. Here, we deliver foundational in vitro evidence that osteosarcoma cell-derived EVs drive myofibroblast/cancer-associated fibroblast differentiation. Human lung fibroblasts displayed increased invasive competence, in addition to increased α-smooth muscle actin expression and fibronectin production upon EV treatment. Furthermore, we demonstrate, through the use of transforming growth factor beta receptor 1 (TGFBR1) inhibitors and CRISPR-Cas9-mediated knockouts, that TGFβ1 present in osteosarcoma cell-derived EVs is responsible for lung fibroblast differentiation. Overall, our study highlights osteosarcoma-derived EVs as novel regulators of lung fibroblast activation and provides mechanistic insight into how osteosarcoma cells can modulate distant cells to potentially support metastatic progression.
- Published
- 2020
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