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Signal integration and rewiring during tumor development

Final Report Summary - P38CANCER (Signal integration and rewiring during tumor development)

Cell fate decisions rely on signaling pathways that integrate external cues to coordinate specific intracellular programs. One of these pathways leads to the activation of the protein kinase p38a, which plays key roles in cell responses to environmental stresses as well as to chemotherapeutic agents and oncogenes. Importantly, p38a acts in a context- and cell type-specific manner to integrate signals that control cell proliferation, differentiation and survival. There is good evidence indicating that p38a activation can negatively regulate malignant cell transformation at different levels, therefore functioning as a tumor suppressor in normal cells. Intriguingly, p38a signaling has been sometimes linked to tumor development.

This project has investigated mechanisms of signal integration by p38a, with special emphasis on how this signaling pathway serves oncogenic functions. We have generated cellular systems to specifically activate or inactivate p38a signaling, which have allowed us to identify networks of phosphorylated proteins and gene expression changes regulated by this pathway. This information has been useful to elucidate key p38a targets in particular processes, and should provide valuable hints to understand the mechanistic basis for the regulation of different cellular responses by p38a. An important part of the studies focused on the mechanisms underlying pro-tumorigenic functions of p38a signaling, including the regulation of cancer cell homeostasis and spreading. Our experimental approach combined genetic manipulations with the use of chemical inhibitors in different mouse and human cell lines. The results obtained using several types of cancer cells support that p38a can control various mechanisms that enable tumorigenesis.

We have generated mouse models that allow the deletion of p38a in a temporal and cell type-specific manner to investigate in vivo functions of this signaling pathway during tumorigenesis. Using these genetic models as well as pharmacological inhibitors, we have analyzed the role of p38a in the regulation of tumor development in different tissues. We have also investigated how p38a regulates the interplay between cancer cells and normal cells in the tumor stroma. Our studies in mouse models showed that p38a signaling contributes to both colorectal and lung tumorigenesis in vivo by facilitating the proliferation and survival of cancer cells. Similarly, we found that p38a plays an important role in breast tumor development in vivo, and p38a inhibitors potentiate the effect of some chemotherapeutic drugs to reduce the size and malignancy of mouse and human breast tumors. In addition, p38a signaling controls the production of extracellular factors that modulate the interaction between tumor cells and normal cells of the stroma, which in turn play important roles in tumor development and spreading. Our results indicate that p38a signaling in stromal cells can facilitate tumor development.

Taken together, this project provides interesting insights into how complex signaling networks integrate during tumor development. Importantly, by advancing our knowledge on the functions regulated by p38a signaling, we provide guidance to develop novel cancer therapies based on the use of currently available drugs that target the p38a pathway.