A Translational Approach to the Metastatically Relevant MicroRNA-Landscape

This lecture will present our most actual data on systematically defining the metastasis-associated microRNA landscape in a translational research approach. We profiled and validated microRNA and mRNA expression in a unique series of human colorectal metastasis tissues together with their matched primary tumors and corresponding normal tissues, using these data to guide functional studies. We identified a miR-signature exclusively differentially expressed in metastases with three of these miRs identified as key drivers of an EMT-regulating network acting though a number of novel targets. These include SIAH1, SETD2, ZEB2, and especially FOXN3, which we demonstrated for the first time as a direct transcriptional suppressor of N-cadherin. This had significant impact on migration, invasion, and metastasis in two different in vivo models. The significant deregulation of all players of our network was confirmed in an independent own patient set, and in >6000 patients in a large database of diverse malignancies. Our data define a novel metastasis-orchestrating network with potential impact on the metastatic process in general, based on systematic hypothesis generation from metastasis tissues.

In addition, the lecture will present latest data of the group on single-molecule, single-cell laser superresolution microscopy of micro RNAs in comparison between low- versus highly metastatic cells, as well as first preliminary results on genomic changes found in the same set of resected metastasis and further tissues of the patient series above.