Cell fate decisions rely on signaling pathways that integrate external signals to coordinate specific intracellular programs. One of these pathways leads to the activation of p38α MAPK, which plays key roles in cell responses to many types of stresses as well as chemotherapeutic agents and oncogenes. Importantly, p38α acts in a cell context-specific and cell type-specific manner to integrate signals that affect cell proliferation, differentiation and survival. Evidence from mouse models and human cell lines indicates that p38α can negatively regulate tumor initiation at different levels. Intriguingly, recent results suggest that p38α activation may also sometimes have pro-tumorigenic functions. The molecular basis for the different functions of p38α are not well understood but it is likely that the network of substrates phosphorylated by p38α plays a major role. This project proposes to investigate molecular mechanisms of p38 MAPK signaling during tumorigenesis including the systematic identification of substrates and how they contribute to the different functions of this pathway. An important part of the studies will focus on the mechanisms underlying the rewiring of p38α signaling to serve pro-tumorigenic functions, including in-depth characterization of how p38α regulates the survival, proliferation and spreading of cancer cells, as well as its role in the interplay between cancer cells and stromal cells. We also plan to investigate the implication of p38α in tumor progression in vivo, using both xenografts and genetically modified mice that we have generated to either inactivate or hyperactivate the p38 MAPK pathway. These models will allow us to analyze the role of this signaling pathway in the regulation of tumor initiation, growth and spreading in different tissues. Taken together, this project will address important questions on cellular signaling and tumor development, which might be also useful for more rational anti-tumoral treatments.