Graphene Oxide Promotes Cancer Metastasis through Associating with Plasma Membrane To Promote TGF-β Signaling-Dependent Epithelial-Mesenchymal Transition

Nanomedicines are being developed to treat diverse diseases; however, inadvertent or unintended health effects have to be considered, especially for those targeting cancers. For cancers, occurrence of metastasis hints an advanced phase of cancer progression, and nanomedicines per se should be evaluated for their effects on existing metastatic tumors and triggering metastases. Graphene-based 2D nanomaterials, such as graphene oxide (GO), due to its unique characteristics, have been extensively studied for biomedical applications including cancer therapy. However, the potential effect of GO on metastasis has not been determined yet. Herein, we found that low-dose GO could induce significant morphological and structural changes of the cellular membrane within cancer cells, suggesting an epithelial-mesenchymal transition (EMT), with enhanced invasion/migration and the alterations of representative EMT indicators in GO-treated cells. These changes resulted in enhanced lung metastasis of cancer cells in various metastasis models. The mechanistic investigations unveiled that GO increased the protein levels of the TGF-β receptor, leading to a constitutively activated TGF-β-Smad2/3 signaling pathway that drives the EMT. Collectively, our findings enhance the understanding of the unintended side and detrimental effects of GO nanosheets in increasing the progression of metastatic tumors. Thus, the likelihood of pro-EMT effects upon low-dose GO exposure should be considered when developing GO nanomedicines.