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

治疗药物反应的肿瘤内异质性是已知的现象，并且有助于癌性疾病的耐药性和复发。核因子-κ B（NF-κ B）是一种重要的细胞死亡和存活的转录调节因子，参与肿瘤的发生和化疗耐药。最近的证据表明，NF-κ B也可能促进肿瘤细胞死亡，特别是在程序性细胞死亡的非凋亡类型的情况下。调节NF-κ B已被提出作为抗癌治疗中有前途的策略。然而，到目前为止，临床结果相当令人失望。因此，NF-κ B作为促或抗死亡因子的独特机制和情况需要进一步defined.The项目的目的是阐明NF-κ B在调节个体癌细胞对化疗的异质性反应中的作用。使用基于活细胞显微镜的创新生物学实验，我们将对细胞命运进行分类，并在单个癌细胞水平上监测NF-κ B的动态。结合尖端的生物信息学，这种系统的方法将有助于预测药物反应，并探索NF-κ B信号转导的动力学作为抗癌治疗的潜在靶点。最终，我们的研究结果将对建立治疗反应的临床生物标志物，并开发新的NF-kappaB靶向策略以克服异质性肿瘤的耐药性具有重要意义。

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.