Dr. Constantinos Demetriades

Research Area: Cell Growth control in Health and age-related Disease

Website:  http://www.age.mpg.de/science/research-labs/demetriades/

1. Research Background:

Cell growth is a crucial and tightly regulated process. Cells uptake nutrients from their environment (such as amino acids, sugars, and lipids) and use them to synthesize various macromolecules, which they incorporate to increase their mass and grow. As growth is very energy consuming, cells have developed mechanisms to sense environmental conditions and to adjust their metabolism accordingly, so that they only grow when conditions are optimal. These mechanisms are of great importance, as dysregulation of growth often leads to life-threatening disorders, such as cancer and other agerelateddiseases.

The mTOR kinase, as part of the mTOR complexes 1 (mTORC1) and 2 (mTORC2), is a master growth regulator. It functions as a sensor and a molecular rheostat that links the information from the cellular milieu to the growth properties of the cells. A large number of inputs converge on mTORC1 to regulate growth. Nutrients, energy, and growth factors activate this complex, whereas various stresses strongly inhibit its activity. Besides cell growth, mTOR activity affects the majority of cellular functions and can therefore influence organismal health, lifespan and ageing. Importantly, mutations on upstream path

way components, such as the inhibitory Tuberous Sclerosis Complex (TSC) proteins, can lead to mTOR hyperactivation and, thus, are clinically relevant. Consequently, a number of pharmacological inhibitors that target components of the mTOR network are currently applied to the clinic for the treatment of mTOR-related diseases.

2. Research questions addresses by the group:

Our research aims to investigate the underlying molecular and cellular mechanisms of cell growth control in ageing and disease, mainly by studying how the TSC and mTOR complexes are regulated. We pay great attention to the ‘critical details’ in our experimental results and in the literature, and often discover novel important mechanistic processes in these pathways. We follow approaches to identify new components and/or regulators of the TSC/mTOR complexes, and functionally characterize these genes/proteins, focusing on their putative implementation as new targets for drug development. Our work addresses multiple fundamental questions: How is cell growth regulated in normal cells? How does its dysregulation contribute to the development of cancer and other agerelated diseases? How do cells sense the presence or absence of nutrients, to regulate growth? How is information from multiple diverse signals integrated to regulate TSC/mTOR? How are these protein complexes regulated in a spatiotemporal and tissue-specific manner?

3. Possible projects:

Multiple projects are available in the lab for the prospective PhD students, for most of which we already have intriguing preliminary results. Our philosophy is that each person should have a tailored project based on his/her technical skills and research background, so that he/she is maximally efficient. Although it does not cover the full array of research taking place in our lab, an indicative list is hereby provided:

  • Novel molecular players and mechanisms in amino acid sensing via mTORC1.
  • Characterization of novel mTOR and cell growth regulators in ageing and disease.
  • Role of the TSC/mTOR signaling axis in neurological disorders.
  • Spatiotemporal regulation of the TSC complex in response to starvation and stress stimuli.
  • Investigating the applicability and mode of action of pharmacological mTOR inhibitors in cancer cells.

4. Applied Methods and model organisms:

Our work combines highthroughput Omics approaches along with elegant molecular biology, biochemistry, cell biology and high resolution microscopy techniques. We perform functional genomic RNAi screens to identify novel mTOR and cell growth regulators; we make use of proteomic massspectrometry analyses to discover novel interaction partners for our proteins/complexes of interest; we then combine our findings with state-of-theart methods to characterize the functional role of these genes/proteins and to elucidate the cellular and molecular mechanisms via which they regulate mTOR function and cell growth.

We make use of established human, mouse and Drosophila  cell lines, to identify evolutionarily conserved processes and to address multiple fundamental questions. Our group also implements patientderived cell lines to study the disease relevance of our findings. In order to investigate how our genes of interest affect organismal physiology, behaviour, health and ageing, we often transfer our findings to the mouse model, using wild-type of knock-out animals.

5. Desirable skills and qualifications:

The applicant is required to hold a master’s degree/diploma in biology, biochemistry or a related field, and to have strong written and oral communication skills. The working language of the lab is English; knowledge of the German language is not necessary. Experience in one or more of the following methodologies: cell culture, confocal microscopy, protein (western blotting, immunoprecipitation) and RNA analysis (RT-qPCR), mass-spectrometry, or previous work with mouse models is an advantage.

6. References:

  • Demetriades, C.# , Doumpas, N., and Teleman, AA# . (2014) Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2. Cell. 156(4):786-99.
  • Demetriades, C.# , Plescher, M., and Teleman, AA.#  (2016) Lysosomal recruitment of TSC2 is a universal response to cellular stress. Nature Communications. 7:10662.
  • Plescher, M., Teleman, AA.# , and Demetriades, C.#  (2015) TSC2 mediates hyperosmotic stressinduced inactivation of mTORC1. Scientific Reports. 5:13828.
  • Tsokanos, F.*, Albert, MA.*, Demetriades, C.*, Spirohn, K., Boutros, M., and Teleman, AA. (2016) eIF4A inactivates TORC1 in response to amino acid starvation. EMBO J. 35(10):1058-76.
  • Romero-Pozuelo, J., Demetriades, C., Schroeder, P., and Teleman, AA. (2017) CycD/Cdk4 and Discontinuities in Dpp Signaling Activate TORC1 in the Drosophila Wing Disc. Dev Cell. 42(4):376-387.e5

* Co-first authors

# Co-corresponding authors