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.
Highlights
Osteosarcoma is an aggressive primary bone malignancy mainly affecting children and adolescents [1]
The presence of extracellular vesicles (EVs)-associated markers such as CD63 and CD81 was detected through flow cytometry analysis of EV-coated aldehyde-sulphate beads (Figure 1C). 143-B EVs were subjected to iodixanol density gradient centrifugation, and the expression of additional EV markers CD9 and ALIX was detected in the gradient fractions corresponding to densities between 1.14 and 1.20 g/mL by Western blotting (Figure 1D)
The premetastatic niche (PMN) establishment is associated with stromal changes, including the perturbation of endothelial cell function, the reprogramming of stromal cells, extracellular matrix (ECM) remodeling and the recruitment of several cell populations to secondary organ sites [9]
Summary
Osteosarcoma is an aggressive primary bone malignancy mainly affecting children and adolescents [1]. The major cause of death in osteosarcoma patients, are detectable already in 20% of patients at diagnosis and the majority of patients with localized disease develop metastases later on. The identification of molecular therapeutic targets has been challenging due to the significant degree of tumor heterogeneity, genomic instability and a high frequency of chromothripsis in osteosarcoma cells. It is well established that the interplay between the tumor and stromal cells within the local and distant tumor microenvironment plays a pivotal role in cancer progression and metastasis [4]. The non-cancer stromal cells within the tumor are genetically stable, and, targeting these normal cells and their interactions with tumor cells might offer a more efficient strategy to treat metastatic disease
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