Development of alternative systems for studying drug resistance in cancer

Authors

• MM Gottesman
• W Wulftange
• F Ali-Rahmani
• A Robinson
• L Huff
• A Jaeger
• N Morgan
• TJ Pohida
• K Tanner
• R Robey

Abstract

The Laboratory of Cell Biology has a longstanding interest in developing models to study drug resistance mechanisms, including intrinsic and acquired resistance to anti-cancer drugs and resistance mediated by physiological barriers such as the blood-brain barrier (BBB). While cell line models have long been used to model drug resistant tumors or transporters at the BBB, they do not adequately recapitulate the clinical situation (Gillet et al. PNAS 108: 18708, 2011). We have developed a bioreactor allowing moderately high-throughput measurements on 3D cultures maintained in controllably hypoxic or normoxic conditions, with gradients of oxygen concentration similar to those found in tumors. To accomplish this, an oxygen-transmissive membrane is patterned with a micropillar array, with the pillar spacing similar to typical intercapillary distances. By incorporating this membrane into a bioreactor as a partition between two chambers with independent oxygen control, it is possible to maintain cells in controllable hypoxia over an extended volume around the pillars, thus providing a more physiologically relevant tumor model. A second approach has been to use the zebrafish BBB as a model system for studying how anti-cancer drugs get into the brain. P-glycoprotein (P-gp) and ABCG2 are the two main ATP binding-cassette transporters at the BBB that keep hydrophobic chemotherapeutic agents out of the brain. Initial studies suggest that zebrafish Abcb4 most closely resembles human P-gp and that zebrafish Abcg2c most closely resembles human ABCG2. Studies to further characterize the zebrafish homologs of human transporters and to localize these transporters to the zebrafish BBB are ongoing.

Scientific Focus Area: Institute, Center, and Scientific Directors

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