Molecular switches in the TGFβ signaling pathway – the link to metabolism and the role of inositol pyrophosphate messengers.
Cancer development is characterized by deregulated proliferation and gradual epithelial-to-mesenchymal transition (EMT), a process that exhibits a particularly high energy demand and fosters invasiveness. Transforming growth factor beta (TGFβ) has a dual role in cancer development and acts at early stages as tumor suppressor exerting anti-proliferative effects, while at advanced stages it is a major inducer of EMT. TGFβ-induced EMT is accompanied by an increase in cytosolic ATP, and a group of metabolic messengers termed inositol pyrophosphates (PP-InsPs) are directly tied to ATP availability. PP-InsPs have also been linked to tumor cell migration and metastasis.
To uncover the potential intersection of TGFβ signal transduction and PP-InsPs, AG Fiedler and AG Klingmüller have advanced a multidisciplinary set of chemical biology tools and mass-spectrometry based methods during the last funding period. When PP-InsP levels were substantially reduced in the lung adenocarcinoma cell line H1975, the invasive properties of the cells were impaired and the enhancement of invasiveness through TGFβ stimulation in these cells was strongly reduced. Intriguingly, lowered PP-InsP levels correlated with a sustained induction of immediate early TGFβ target genes, whereas the expression of EMT markers, which are regarded as late TGFβ target genes, was massively reduced. Based on PP-InsP interaction data, we propose that SMAD complex formation - and its recruitment of transcriptional co-factors – can be modulated by PP-InsPs, which distinctly impacts the expression of target genes. This hypothesis will now be tested from the biochemical to the systems level. A parallel putative pathway contributing to invasiveness is TGFb dependent protein pyrophosphorylation, which will be annotated and integrated with time-resolved proteomics data.
Building on these data, we will expand our dynamic model of TGFβ signal transduction to include the influence of PP-InsPs to potentially highlight the switch from tumor suppressive to tumor promoting TGFβ effects. Taken together, we aim at resolving molecular mechanisms that link metabolism and TGFβ signal transduction, and thereby identify novel mechanisms contributing to cancer development, which could be therapeutically harnessed in the future.
Prof. Dr. Dorothea Fiedler (FMP Berlin)
Prof. Dr. Ursula Klingmüller (DKFZ Heidelberg)