Mechanisms of early metastatic spread: Epigenetic plasticity and selection of advantageous genotypes
Final Report Abstract
While metastatic dissemination has long been hold to be a late step in cancer progression, we found that the relative number of disseminating cancer cells is highest at early stages of transformation and that the absolute number of disseminating cancer cells does not or only marginally increase whereas the total tumor mass increases several hundred fold. We then found that mammary epithelial cells of transgenic Balb-neuT mice display progression specific gene expression patterns and therefore investigated whether a gene expression pattern exist for the stage of atypical hyperplasia (ADH) that differs from that of advanced tumours and metastases. We reasoned that this expression pattern might be linked to the propensity to disseminate. We identified such a signature and found that among the several hundred differentially expressed genes, many of them are regulated by the steroid hormones progesterone and testosterone. Using a surrogate signature of genes upregulated at the stage of ADH, we now have an assay to search for the responsive cells and the mechanisms of signal transduction. Once we have identified a cell type that is particularly responsive to the dissemination-inducing signal, we will move on to identify factors that trigger transitions between migrating and stationary-proliferating states. This may identify relevant mechanisms of metastatic dissemination and colony formation at distant sites.
