Notch crosstalk in cancer

The specific focus of this project is to understand how Notch responds to inherent changes in the tumour environment or changes occuring as a consequence of treatment, and how such “tumour stress” influence Notch activity to drive the disease. We have recently identified a Notch-hypoxia crosstalk of relevance for tumor progression (Sahlgren et al., 2008). We have shown that Notch signaling converts hypoxia inherent to the tumor microenvironment into epithelial mesenchymal transition (EMT) required for the hypoxia-induced invasiveness of epithelial tumor cells. We have participated in a project to elucidate the Notch-hypoxia transcriptome to gain insight in how such a crosstalk is manifested on the transcriptome level and to obtain a molecular platform to better understand the intersection between the two signaling cascades in normal development and cancer (Main et al., 2010).  More recent data from the lab show that there is an elaborate crosstalk between Notch and cell metabolism and that Notch is important for metabolic flexibility. Metabolic flexibility is one of the hallmarks of cancer and metabolic “transformation”  helps cancer cells to survive and drives aggressive metastatic cancer. Preliminary data also indicate that Notch functions as a sensor for metabolic constrains. Based on our observations we propose that Notch functions as the cells survival artist by sensing environmental and metabolic stress and providing cells with various mechanisms to counteract these challenges.  The key goal is to understand how Notch gets derailed in cancer and how derailed Notch signaling influence the progression of the disease.