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
|
|