Berlin 2018 – wissenschaftliches Programm
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BP: Fachverband Biologische Physik
BP 5: Systems Biology & Gene Expression and Signalling
BP 5.1: Vortrag
Montag, 12. März 2018, 15:00–15:15, H 1028
Mathematical modeling of drug-induced receptor internalization in breast cancer cells — •Mirjam Fehling-Kaschek1, Diana Peckys2, Jens Timmer1, and Niels de Jonge3 — 1University of Freiburg — 2Department of Biophysics, Saarland University — 3Leibniz Institute for New Materials, Saarbrücken
About 20% of breast cancer tumors over-express the HER2 receptor. Trastuzumab, an approved drug to treat this type of breast cancer, is an antibody directly binding at the HER2 receptor and inhibiting cell growth. The goal of our study was to understand the early impact of trastuzumab on HER2 internalization and recycling in the HER2-positive SKBR3 cell line. To this end, single cell fluorescence microscopy, monitoring the state of HER2 expression on the membrane, was combined with mathematical modeling to derive the flux of HER2 receptors from and to the membrane. We constructed a dynamic multi-compartment model based on ordinary differential equations to account for intracellular HER2 production and distribution of HER2 receptors between membrane ruffles and flat regions of the cell by internalization and recycling processes. To account for the heterogeneity in cell size and HER2 expression in SKBR3 cells, the dynamic model was expanded to a mixture model. The model describes the experimental observation that drug induced receptor internalization occurs preferentially in cells containing membrane ruffles, while internalization in non-ruffled cells happens at a much smaller rate. Our analysis shows that the common hypothesis of constitutive HER2 recycling back to the plasma membrane is not supported by the data.