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Open AccessArticle

Osteosarcoma-Derived Extracellular Vesicles Induce Lung Fibroblast Reprogramming

1
Department of Orthopedics, Balgrist University Hospital, CH-8008 Zurich, Switzerland
2
Institute for Biomechanics, ETH Zurich, CH-8008 Zurich, Switzerland
3
Department of Oncology, Children’s Research Center, University Children’s Hospital Zürich, CH-8032 Zurich, Switzerland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(15), 5451; https://doi.org/10.3390/ijms21155451
Received: 9 July 2020 / Revised: 23 July 2020 / Accepted: 29 July 2020 / Published: 30 July 2020
(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment)
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. View Full-Text
Keywords: osteosarcoma; extracellular vesicles; lung fibroblasts; tumor microenvironment; tumor-host interactions osteosarcoma; extracellular vesicles; lung fibroblasts; tumor microenvironment; tumor-host interactions
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Mazumdar, A.; Urdinez, J.; Boro, A.; Migliavacca, J.; Arlt, M.J.; Muff, R.; Fuchs, B.; Snedeker, J.G.; Gvozdenovic, A. Osteosarcoma-Derived Extracellular Vesicles Induce Lung Fibroblast Reprogramming. Int. J. Mol. Sci. 2020, 21, 5451.

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