„Systems medicine” van het mTOR en metabole netwerk bij TSC.

Systems medicine” van het mTOR en metabole netwerk bij TSC.

Prof. Dr. Kathrin Thedieck, Universitair Medisch Centrum, Groningen.

The mammlian target of rapapmycin (mTOR) signaling network is a prime drug target in tuberous scerlosis complex (TSC), as well as in many malignant tumor diseases. mTOR is embedded in complex kinase signaling and metabolic networks, which are often altered in TSC1/2 deficient cells as well. Examples are glucose metabolism, redox signaling, or the TGFbeta signaling network. The tuning of these networks can be different in individual patients and in different tumors. Due to the complex wiring of tumor signaling and metabolism, drug responses can often not be intuitively predicted, and drugs can even elicit paradox effects, i.e. induce cellular growth where they would be expected to inhibit it. This makes it challenging to predict the response of individual patients to mTOR inhibitors, and to design combinatorial therapies with other compounds to maximize the effects of mTOR inhibitors.

To unravel this complexity, we develop computational models to simulate and predict the response of mTOR and the ancillary signaling and metabolic networks to drug treatments. Using this approach, we have shown previously that the second mTOR complex, mTORC2, is not directly regulated by the TSC1-TSC2 complex, and that the tumor suppressor AMP-dependent kinase (AMPK) plays a surprising, active role upon growth factor stimulation. We now embark to extend our modeling approaches to predict drug responses in tumors. In this talk our most recent advances will be presented.

 

Referenties relevante/recente publicities:

Schwarz JJ*, Wiese H*, Toelle RC, Zarei M, Dengjel J, Warscheid B§, Thedieck K§.

Functional proteomics identifies acinus L as a direct insulin- and amino acid-dependent mTORC1 substrate. Mol Cell Proteomics. 2015 Aug;14(8):2042-55.

Thien, A*, Prentzel, MT*, Holzwarth, B, Klaesener, K, Kuper, I, Boehlke C, Sonntag A G, Ruf S, Maerz L, Nitschke R, Grellscheid SN, Reth M, Walz G, Baumeister R, Neumann-Haefelin E§, Thedieck K§ TSC1 activates TGF-β - Smad2/3 signaling in growth arrest and epithelial to mesenchymal transition. Developmental Cell. (2015) Mar 9; 32 (5):617–630

Thedieck K§, Holzwarth B, Prentzell MT, Boehlke C, Kläsener K, Ruf S, Sonntag AG, Maerz L, Grellscheid SN, Kremmer E, Nitschke R, Kuehn EW, Jonker JW, Groen AK, Reth M, Hall MN, Baumeister R. Inhibition of mTORC1 by Astrin and Stress Granules Prevents Apoptosis in Cancer Cells. Cell. (2013) 154, 859-874.

Dalle Pezze P*, Sonntag AG*, Thien A, Prentzell MT, Gödel M, Fischer S, Neumann-Haefelin E, Huber TB, Baumeister R, Shanley DP§, Thedieck K§ A Dynamic Network Model of mTOR Signalling Reveals TSC-Independent mTORC2 Regulation. Science Signalling (2012) 27 March Vol 5 Issue 217 ra25

Sonntag AG*, Dalle Pezze P*, Shanley DP§, Thedieck K§ A modelling-experimental approach reveals insulin receptor substrate (IRS)-dependent regulation of adenosine monosphosphate-dependent kinase (AMPK) by insulin.

FEBS Journal (2012) Sep;279(18):3314-3328.