J. Swanner, C.D. Fahrenholtz, P.-A. Vidi, K.L. Cook, M. McMahon, I. Tenvooren, B.W. Bernish, J.J. Sears, G.L. Donati, R.N. Singh
Wake Forest School of Medicine,
Keywords: epithelial-mesenchymal transition, EMT, ZEB1, nanoparticle, TNBC, controlled release, reactive oxygen, therapeutics, therapy, in vivo
Summary:Acquisition of a high-mesenchymal cell state by human tumors and cancer cell lines leads to increased cellular plasticity and may contribute to development of cancer drug resistance and tumor recurrence. Expression of zinc finger E‐box binding protein 1 (ZEB1), a transcriptional regulator, drives a mesenchymal cancer cell state and enables cells to survive under the stress of oncogenic transformation. ZEB1 can induce epithelial-mesenchymal transition (EMT) by transcriptional repression of the epithelial splicing regulatory protein 1 (ESRP1). Moreover, repression of ESRP1 is associated with high risk of metastasis in early breast cancer. ZEB1 also represses E-cadherin and is linked to increased expression of mesenchymal markers such as N-cadherin and vimentin. As cancers progress, ZEB1 expression causes increased cellular motility, induction of stem-cell like features, resistance to therapy, metastasis, and subsequently poor outcomes in breast, lung, ovarian, and colorectal, and other cancers. Thus, selective treatment of mesenchymal, ZEB1 expressing cancer cells is emerging as an exciting approach to address cancer heterogeneity and therapy resistance. We establish that increased mRNA expression of the transcription factor ZEB1 (zinc finger E-box binding homeobox 1) defines a mesenchymal subset of breast, ovarian, lung, colorectal, and prostate cancers that is extremely sensitive to exposure to silver nanoparticles (AgNPs). Mechanistically, AgNPs are rapidly ionized in ZEB1high cancer cells due to elevated baseline levels of reactive oxygen species (ROS) that cause dissolution of AgNPs to release Ag+, which then causes cell death. AgNPs deplete cellular antioxidants and cause endoplasmic reticulum stress in ZEB1high breast cancer cells without causing similar damage in ZEB1low, non-cancerous breast epithelial cells. AgNPs also cause extensive DNA damage in in ZEB1high breast tumor nodules, but do not disrupt the normal architecture of breast acini in 3D cell culture, nor cause DNA damage or induce apoptosis in these structures. Intravenous administration of AgNPs effectively treats a ZEB1high breast cancer xenograft in nude mice. Our discovery that ZEB1 is a biomarker that can predict which cancers are most likely to respond to AgNP therapy increases the possibility of future human clinical trials of AgNPs by reducing the potential risk and increasing the potential benefit for well-selected patients. Our future goals are two-fold: (1) to build upon the unique interaction of AgNPs with ZEB1high/ESRP1low cancers to determine which properties of the nanomaterial or the cancer target are important to retain or enhance this selective cytotoxic activity, (2) and to improve the pharmacokinetic and tumor uptake profile of the nanoparticles. Ultimately, we seek to translate our discovery to develop new, AgNP-based cancer therapeutics.