Signal transduction is a multistep process that is dependent on the tissue type, cell type, signal type and location of individual components. Picture signal transduction as a game of telephone: It can start gentle as a whisper or demanding like a scream, with all possibilities in between. The second player has the choice how to talk to the next player, allowing for modifications in signal strength by amplification, stepping closer to the next player, or even transferring the information to not only one but multiple players. Thus, one single initial signal, usually a ligand binding its specific receptor, can lead to a multitude of outcomes. These complex signaling cascades comprise unique players that are essential to finish the game but also redundant players that can be skipped if necessary. It is important to note that every player can add their own flavor to the game, making signal transduction a highly adaptable and dynamic process. Signal transduction, and thus the telephone game, ends in altered cell behavior.
In cancerous diseases, the natural tissue maintenance of the respective organ is altered. Cancer cells differ from normal cells by altering how they respond to certain external stimuli. The Transforming Growth Factor beta (TGFβ) pathway is important in embryonic development and in wound healing processes, but remains silent in the healthy adult pancreas. In pancreatic cancer, the TGFβ pathway is highly activated leading to a multitude of contradicting changes in cell behavior. The TGFβ ligand is binding its receptor on the cell surface, starting a signal that is passed on to receptor-activated proteins called SMAD2/3 that bind to SMAD4. This complex then translocates into the nucleus to bind the DNA strand and initiate gene transcription. However, loss of SMAD4 is a common event in pancreatic cancer and strongly associated with increased cancer growth.
In this study, I compared the behavior of cancer cells with the same genetic background only differing in their expression of SMAD4 when exposed to TGFβ ligand. We identified that loss of SMAD4 leads to the TGFβ-mediated activation of a completely new group of target genes. Direct comparison showed that SMAD4-deficient cells are more resistant than their counterparts to a chemotherapeutic agent used to treat metastatic pancreatic cancer. Importantly, we also identified specific sensitivities to other chemotherapeutic agents due to the loss of SMAD4. This work details the quest to elucidate alternative TGFβ-induced signal transduction in the context of SMAD4 deficiency and identifies altered cellular behavior and responses to chemotherapeutic agents. Identifying the contribution of genetic mutations to cellular responses is another important milestone on our path to enhancing cancer treatment strategies and improving pancreatic patient care through personalized medicine approaches.
