Junior Group Cellular Toxicology

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Dr. Cristina Cadenas Garcia / Dr. Rosemarie Marchan

The CellTox group was established in January 2013 under the supervision of Cristina Cadenas and Rosemarie Marchan with the goal to better understand how cells respond to different types of stress. Both scientists are especially interested in cellular metabolism, with particular focus on lipid and choline metabolic pathways. A major goal of their work is therefore to elucidate how metabolism is altered in in response to cellular stressors as well as in disease.

Lipids are important membrane constituents, energy sources, and signalling molecules – all of which are essential for maintaining cellular homeostasis, and are thus relevant in the context of cellular damage. Initially, the CellTox group studied lipid metabolism in connection with cancer and cellular senescence, with the goal to better characterise genes regulating phospholipid and choline metabolic pathways. This led to the identification of a previously uncharacterized enzyme that appears to be relevant for both aforementioned pathways: glycerophosphocholine glycerophosphodiesterase 1 (GPCPD1, EDI3) (Stewart et al., 2012; Marchan et al., 2012). Ongoing studies still explore GPCPD1 and related enzymes in relation to cancer and cancer-related phenotypes (Lesjak et al., 2014), acetylcholine production, glucose metabolism, and cellular homeostasis. A second enzyme, the endothelial lipase (LIPG), which cleaves phosphatidylcholine in extracellular lipoproteins, was initially found to be upregulated in a model of oncogene-induced senescence (Cadenas et al., 2012). Current studies of the group include the characterisation of LIPG expression in breast cancer patients and tumour cell lines upon oxidative stress and indicate LIPG upregulation as an adaptive mechanism to metabolic stress conditions. With its growing expertise in lipid metabolism, recent work in CellTox is also focussed on the highly relevant non-alcoholic fatty liver disease (NAFLD), with the aim to understand how chronically increased fatty acid influx into the liver results in metabolic alterations that compromise liver function (Kessler et al., 2014; Gogiashvili et al., 2016).

Over the years, members of the CellTox group have developed and implemented several different techniques that allows the systematic evaluation of cellular responses upon stress stimuli. Other activities by the group include: i) collection of clinically-available patient datasets, and establishment of in vivo and in vitro relevant models of fatty liver disease and cancer to address scientific questions; ii) generation and statistical analysis of transcriptomics data of these models for understanding cell behaviour at the transcriptional level (in collaboration with the Statistics Department at the TU Dortmund); and iii) establishment of close collaborations with the Analytical Chemistry Unit at IfADo and with local and regional partners (ISAS Dortmund and University of Münster) for the quantification of relevant lipid species and key metabolic intermediates by NMR or mass spectrometry-based methods. CellTox also works closely with other groups within the institute, as well as maintaining fruitful collaborations with both scientists both nationally and internationally.

Third-party funds

Financial year

Funding source

2012-2015

EU, Body on a Chip*

2012-2017

BMBF, DEEP*

2016-2019

DFG (HE2509)

* shared with research group ‘Systems Toxicology‘

Publications:

Gogiashvili M, Edlund K, Gianmoena K, Marchan R, Brik A, Andersson JT, Lambert J, Madjar K, Hellwig B, Rahnenführer J, Hengstler JG, Hergenröder R, Cadenas C. Metabolic profiling of ob/ob mouse fatty liver using HR-MAS (1)H-NMR combined with gene expression analysis reveals alterations in betaine metabolism and the transsulfuration pathway. Anal Bioanal Chem. 2016 Nov 28. [Epub ahead of print].

Kessler SM, Simon Y, Gemperlein K, Gianmoena K, Cadenas C, Zimmer V, Pokorny J, Barghash A, Helms V, van Rooijen N, Bohle RM, Lammert F, Hengstler JG, Mueller R, Haybaeck J, Kiemer AK. Fatty acid elongation in non-alcoholic steatohepatitis and hepatocellular carcinoma. Int J Mol Sci. 2014 Apr 4;15(4):5762-73. doi:10.3390/ijms15045762.

Cadenas C, Vosbeck S, Hein EM, Hellwig B, Langer A, Hayen H, Franckenstein D, Büttner B, Hammad S, Marchan R, Hermes M, Selinski S, Rahnenführer J, Peksel B, Török Z, Vígh L, Hengstler JG. Glycerophospholipid profile in oncogene-induced senescence. Biochim Biophys Acta. 2012 Sep;1821(9):1256-68. doi:10.1016/j.bbalip.2011.11.008.

Lesjak MS, Marchan R, Stewart JD, Rempel E, Rahnenführer J, Hengstler JG. EDI3 links choline metabolism to integrin expression, cell adhesion and spreading. Cell Adh Migr. 2014;8(5):499-508. doi: 10.4161/cam.29284.

Stewart JD, Marchan R, Lesjak MS, Lambert J, Hergenroeder R, Ellis JK, Lau CH, Keun HC, Schmitz G, Schiller J, Eibisch M, Hedberg C, Waldmann H, Lausch E, Tanner B, Sehouli J, Sagemueller J, Staude H, Steiner E, Hengstler JG. Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis. Proc Natl Acad Sci U S A. 2012 May 22;109(21):8155-60. doi: 10.1073/pnas.1117654109.

Marchan R, Lesjak MS, Stewart JD, Winter R, Seeliger J, Hengstler JG. Choline-releasing glycerophosphodiesterase EDI3 links the tumor metabolome to signaling network activities. Cell Cycle. 2012 Dec 15;11(24):4499-506. doi: 10.4161/cc.22544.