SynthesisThe risk of most cancer types increases exponentially with aging. This proposal is focused on the role of the tumor microenvironment in this context, at the interface between aging and cancer development. Subjects and ObjectivesOur main objective is to dissect the function of the CSL protein, the effector of canonical Notch signaling, in stromal cell senescence and Cancer Associated Fibroblast activation. We will be testing a cancer/stromal co-evolution model with CSL and p53 as co-determining factors and explore the clinical significance of the findings.Socio-scientific contextAge-dependent increase of cancer and recurrent epithelial tumors are major causes of morbidity and mortality. Development of epithelial cancer can result from an altered tissue microenvironment. Our work on this topic is of substantial socio-scientific relevance, as it may lead to novel preventive and therapeutic approaches to the cancer problem.

Lay summary

??Epithelial-mesenchymal interactions play a determining function in organ morphogenesis, tissue homeostasis and carcinogenesis. Notch signaling is an important form of cell-cell communication with a key role in control of cell fate commitment. The role of this pathway in the epithelial cell compartments of organs like the skin is by now well established. In our previous work we have demonstrated that it plays an equally important tumor suppressing function in the mesenchymal compartment. As a continuation of our work, we are now planning to dissect the underlying molecular mechanisms, focusing on CSL, a transcriptional repressor and key effector of Notch activation, which can also function independently of Notch activation through binding to other transcription factors and/or modulators of gene expression. Activation of cancer associated fibroblasts (CAFs) has been linked with stromal cell senescence and autophagy. Yet, very little is known on how these processes are commonly controlled.  We will be testing the hypothesis that CSL acts as a negative regulator of these processes through functional and biochemical interactions with other key cellular regulatory proteins, specifically p53.