Max Planck Research Group Demetriades

Cell Growth Control in Health and Age-related Disease

Because nutrients are the building blocks for cells to grow and proliferate, nutrient sensing mechanisms ensure that cells only grow when all necessary elements are available and all conditions are optimal. Our work focuses on the intricate molecular and cellular mechanisms that govern cellular growth, metabolism and secretion upon starvation and stress, mainly via the regulation of the TSC/mTOR signaling hub. Given the central role of mTOR in the ageing process—and that dysregulation of the nutrient sensing machinery is a hallmark of ageing—our research investigates fundamental aspects of ageing and age-related diseases.

The mTOR kinase, primarily as part of the mTOR complex 1 (mTORC1), is the 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 cells (reviewed in Fernandes & Demetriades, 2021 Front Aging). A large number of inputs converge on mTORC1 to regulate growth. Besides cell growth, mTOR activity affects the majority of cellular functions and can therefore influence organismal health, lifespan and ageing. Importantly, mutations on upstream pathway components, such as the tumor suppressor Tuberous Sclerosis Complex (TSC) proteins, can lead to mTORC1 hyperactivation, and, thus, are clinically relevant.

Our research sheds light on existing and novel molecular mechanisms of cell growth control, mainly via the regulation of TSC/mTORC1, and aims to identify and functionally characterize novel components and regulators of these complexes, focusing on their putative implementation as new targets for drug development. Given the key role of the TSC/mTOR signaling hub in virtually all cellular processes, we investigate the intricate interplay between nutrient sensing, lysosomal function & signaling, metabolism, protein secretion, and the extracellular proteome.

To achieve this, we combine high-throughput omics approaches (functional genomic screens, proteomics, metabolomics, interactome/proximome analyses) with state-of-the-art molecular biology, biochemistry, cell biology and high-resolution microscopy techniques. We make use of established human and mouse cell lines, cancer cell lines, patient-derived cells, as well as mouse models, to identify evolutionarily conserved processes and to address multiple fundamental questions. In sum, our vision is to understand:

• How cells sense the availability of nutrients in their environment to adjust their growth, metabolism and other functions accordingly,
• How the dysregulation of these cellular mechanisms contributes to the development of human diseases and the ageing process, and
• How we can intervene pharmacologically to target these mTOR-related conditions.

more

Selected publications

Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor
Nicastro, R., Brohée, L., Alba, J., Nüchel, J., Figlia, G., Kipschull, S., Gollwitzer, P., Romero-Pozuelo, J., Fernandes, S.A., Lamprakis, A., Vanni, S., Teleman, A.A., De Virgilio, C., Demetriades, C.
(2023) Nat Cell Biol

A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids
Gollwitzer, P., Grützmacher, N., Wilhelm, S., Kümmel, D., Demetriades, C.
(2022) Nat Cell Biol

An mTORC1-GRASP55 signaling axis controls unconventional secretion to reshape the extracellular proteome upon stress
Nuechel, J., Tauber, M., Nolte, J. L., Morgelin, M., Turk, C., Eckes, B., Demetriades, C., Plomann, M.
(2021) Mol Cell, 81, 16, 3275-3293 

Lysosomal recruitment of TSC2 is a universal response to cellular stress
Demetriades C., Plescher M., and Teleman AA.,
(2016) Nature Communications; 7:10662.

Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2
Demetriades C., Doumpas N., and Teleman AA.,
(2014) Cell.; 156(4):786-99.