Integrins are one of the major cell surface adhesion receptors and are dysregulated in many types of cancers. Prosurvival signaling of integrins causes the resistance to radio- and chemotherapy, therefore, hindering an efficient cancer therapy. As the majority of the cellular factors that contribute to the therapy resistance are not known, we will establish a miniaturized platform that enables efficient identification of such factors in the physiologically-relevant conditions. We will utilize a novel miniaturized Droplet-Microarrays (DMA) for the growth, manipulation and imaging of spheroids resulting from the cancer cells. We will establish experimental settings for combining RNAi targeting of regulators of integrin expression and trafficking with anti-cancer drugs. Specifically, we will deplete the regulators of integrin ?2?1 in breast tumor spheroids to order to identify the proteins that induce integrin-mediated chemical resistance to anti-proliferative reagents; and could be further explored as potential targets for anti-cancer therapy.
After the proof-of-concept phase, the platform will be used for large-scale combinatorial screening involving diverse cellular targets, chemicals and the cellular contexts. Prospectively, the platform will be able to analyze the spheroids made out of the patient cells. The proposed research project directly addresses HEIKA’s focus in the “Research Bridge” Synthetic Biology. In the planned work we combine the novel DMA screening platform, based on surface patterning of a biocompatible polymer, developed at KIT with the scientific and practical expertise in the field of RNA interference, assay development, microscopy and integrin biology carried by Heidelberg University.