Tumor-derived extracellular vesicles (TEVs) induce the epithelial-to-mesenchymal transition (EMT) in nonmalignant cells to promote invasion and cancer metastasis, representing a novel therapeutic target in a field severely lacking in efficacious antimetastasis treatments. However, scalable technologies that allow continuous, multiparametric monitoring for identifying metastasis inhibitors are absent.
Researchers at the University of Cambridge have developed a functional phenotypic screening platform based on organic electrochemical transistors (OECTs) for real-time, noninvasive monitoring of TEV-induced EMT and screening of antimetastatic drugs. TEVs derived from the triple-negative breast cancer cell line MDA-MB-231 induce EMT in nonmalignant breast epithelial cells (MCF10A) over a nine-day period, recapitulating a model of invasive ductal carcinoma metastasis. Immunoblot analysis and immunofluorescence imaging confirm the EMT status of TEV-treated cells, while dual optical and electrical readouts of cell phenotype are obtained using OECTs. Further, heparin, a competitive inhibitor of cell surface receptors, is identified as an effective blocker of TEV-induced EMT. Together, these results demonstrate the utility of the platform for TEV-targeted drug discovery, allowing for facile modeling of the transient drug response using electrical measurements, and provide proof of concept that inhibitors of TEV function have potential as antimetastatic drug candidates.
A model to recapitulate invasive ductal carcinoma
integrated with an OECT platform for monitoring TEV-induced EMT
EMT has been implicated in the initiation of metastasis, as epithelial cells at the invasive front of carcinomas acquire migratory and invasive properties to break through the basement membrane and disseminate via circulation to form metastases in distal organs. Postinternalization, recipient cells exhibit physiological changes associated with alterations of their transcriptome and proteome. TEV exposure results in increased expression of several mesenchymal markers, including vimentin and TWIST1, and decreased expression of epithelial markers, including reciprocal changes in E-cadherin and N-cadherin expression – the so-called cadherin switch. Functionally, TEVs enhance the migratory and invasive properties of recipient cells. By integrating a highly relevant model of breast cancer metastasis associated EMT on OECTs, this malignant process can be monitored in real time with multiparametric readouts and the effect of TEV-targeting drugs can be assessed.