The epithelial-to-mesenchymal transition (EMT) is an evolutionarily conserved process that is required for normal development. However, EMT is often dysregulated and hijacked by cancers during tumor progression. Cancer cells that have undergone EMT and acquired a mesenchymal phenotype harbor several distinct traits, including increased tumor initiating properties, augmented motility, increased metastatic properties, and a higher incidence of resistance to therapy. Therefore, treatment regimens specific to mesenchymal cancer cells would be advantageous. In this study, we discovered that a mesenchymal subpopulation of breast, ovarian, lung, colorectal, and prostate cancer cell lines with high expression of the transcription factor ZEB1 (zinc finger E-box binding homeobox 1) and low expression of epithelial genes repressed by ZEB1 including ESRP1 (epithelial splicing regulatory protein 1) and CDH1 (E-cadherin) are an order of magnitude (>10-fold) more sensitive to exposure to silver nanoparticles (AgNPs) than cells expressing only low levels of ZEB1. This finding is significant because: (i) This is the first time a biomarker has been identified that is predictive of a positive response to any form of engineered nanomaterial; (ii) ZEB1 expression is a marker of poor clinical prognosis, and therefore identification of improved therapeutics for this poor outcome patient population is desirable; (iii) this work establishes that there is a shared and exploitable vulnerability across multiple cancer types that is independent of tissue origin and identifiable based upon mRNA or protein quantification of ZEB1. We establish that the ZEB1high selective cytotoxic properties of biocompatible AgNPs are not achieved using ionic silver, and therefore is one of the first examples of a “new to nano” cytotoxic property. Mechanistically, we find that AgNPs are rapidly ionized in ZEB1high cells, leading to endoplasmic reticulum stress, DNA damage, and apoptotic cell death. Furthermore, we show that AgNPs do not disrupt the normal architecture of breast acini in 3D cell culture, nor do they cause DNA damage. In contrast, the same doses of AgNPs cause extensive DNA damage and apoptosis in ZEB1high breast tumor nodules produced in 3D culture. Induction of EMT using TGF-β increases sensitivity to AgNPs and, conversely, knockdown of ZEB1 desensitizes cells to AgNP therapy. Finally, we demonstrate that systemic administration of AgNPs is safe and effective for treatment of ZEB1high breast cancer orthotopic xenografts in mice. In conclusion, our work provides evidence that a therapeutic window exists for the safe use of AgNPs as a precision medicine for patients with ZEB1-expressing tumors regardless of tissue origin.

Citation Format: Cale D. Fahrenholtz, Jessica Swanner, James Sears, Katherine Cook, Pierre-Alexandre Vidi, Ravi Singh. A mesenchymal subset of cancers with elevated ZEB1 expression is sensitive to low doses of silver nanoparticles [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B123.