Can NF-kappaB be a friend in cancer therapy? A systematic approach to study individual drug responses, and to convert NF-kappaB into a pro-death signal in resistant cancer cells

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Intratumoral heterogeneity in therapeutic drug responses is a known phenomenon and contributes towards resistance and relapse of cancerous diseases. Nuclear factor kappaB (NF-kappaB) is an important transcriptional regulator of cell death and survival, and is involved in carcinogenesis and chemoresistance. Recent evidence suggests that NF-kappaB may also promote tumor cell death, especially in the case of non-apoptotic types of programmed cell death. Modulation of NF-kappaB has been proposed as a promising strategy in anti-cancer therapy. However, so far the clinical outcome is rather disappointing. Thus the distinct mechanisms and circumstances of NF-kappaB as a pro- or anti-death factor need to be further defined.The aim of this project is to clarify the role of NF-kappaB in regulating the heterogeneous responses of individual cancer cells towards chemotherapy. Using innovative biological experiments based on live cell microscopy we will classify cellular fates and monitor the dynamics of NF-kappaB on the level of individual cancer cells. Combined with cutting-edge bioinformatics this systematic approach will help to predict drug responses, and explore the dynamics of NF-kappaB signaling as a potential target for anti-cancer therapy. Ultimately, our results will be significant to establish clinical biomarkers of therapy responses, and develop novel NF-kappaB targeting strategies to overcome drug resistance in heterogeneous tumors.