Abstract

Complex Cell- and Tissue-Based Model Systems for Phenotypic Drug Discovery - Investigating the Functional Role of the Tumor Microenvironment

Matthias Nees, Group Leader, University of Turku

The functional role of the tumor microenvironment  (TME) in tumor progression, sensitivity to chemotherapeutic drugs and development of drug resistance, development of tumor cell invasion and metastasis is still poorly understood – partly because of the lack of appropriate and thoroughly validated in vitro models. The goal of our complex, organotypic cell culture model systems is to provide robust tools to systematically address tumor/stroma and other heterotypic cell-cell interactions in a miniaturized, standardized assay format.

Our assays are designed for phenotypic drug discovery and high content screening approaches. Automated image analysis software tools allow us to address both the tumor morphology (differentiation and maturation of organoids versus invasive processes) and stromal dynamics (e.g. formation of syncytia, contraction and dynamic re-organization of the extracellular matrix) simultaneously.  Tumor cell plasticity can then be observed in real-time, life-cell assays and probed by small molecule inhibitor screens and/or functional genetics (siRNAs and miRNAs).

We will introduce novel high content screening approaches that aim to systematically identify critical cell-cell-interactions as promising targets for anti-cancer therapy. These cannot be easily addressed in standard 2D or 3D monoculture assays. Further, we demonstrate that to understand the biology of tumors and their response to chemotherapy more completely, complex organotypic assays are required that recapitulate many of the dynamic the functions of