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

Field cancerization is a condition of major clinical significance consisting of widespread tissue alterations associated with multiple and recurrent primary tumors. Activation of stromal fibroblasts into cancer associated fibroblasts (CAFs) is most frequently viewed as secondary to changes in the epithelium. However, our previous work indicated that it can play a primary role in epithelial cancer development. We are currently exploring a multistep process of CAF activation and expansion based on a combination of genetic and/or epigenetic events. Whether or not chromosomal changes of functional significance occur in this context remain to be established. In our future work, we will address this question focusing on the role of a specific DNA- binding protein, CSL, in control of chromosome stability and telomere maintenance. CSL expression and function are commonly compromised in CAFs and we will test whether, as a result, these cells acquire specific chromosomal alterations that confer a growth advantage important for cancer stromal cell expansion.