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Jens Marquardt

About Jens Marquardt:
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SEEK ID: https://seek.lisym.org/people/151

Location:  Germany

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LiSyM-Krebs Partnering

This generic project is intended to be a forum for all LiSyM partner and external stakeholders interested in participating in the BMBF initiative LiSyM-Krebs.

Programme: LiSyM-Krebs

Public web page: https://www.ptj.de/projektfoerderung/gesundheitsforschung/lisym-krebs

Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance.
LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI)

Abstract (Expand)

BACKGROUND: The extracellular signal-regulated kinase (ERK) pathway regulates cell growth, and is hyper-activated and associated with drug resistance in hepatocellular carcinoma (HCC). Metabolic pathways … are profoundly dysregulated in HCC. Whether an altered metabolic state is linked to activated ERK pathway and drug response in HCC is unaddressed. METHODS: We deprived HCC cells of glutamine to induce metabolic alterations and performed various assays, including metabolomics (with (13)C-glucose isotope tracing), microarray analysis, and cell proliferation assays. Glutamine-deprived cells were also treated with kinase inhibitors (e.g. Sorafenib, Erlotinib, U0126 amongst other MEK inhibitors). We performed bioinformatics analysis and stratification of HCC tumour microarrays to determine upregulated ERK gene signatures in patients. FINDINGS: In a subset of HCC cells, the withdrawal of glutamine triggers a severe metabolic alteration and ERK phosphorylation (pERK). This is accompanied by resistance to the anti-proliferative effect of kinase inhibitors, despite pERK inhibition. High intracellular serine is a consistent feature of an altered metabolic state and contributes to pERK induction and the kinase inhibitor resistance. Blocking the ERK pathway facilitates cell proliferation by reprogramming metabolism, notably enhancing aerobic glycolysis. We have identified 24 highly expressed ERK gene signatures that their combined expression strongly indicates a dysregulated metabolic gene network in human HCC tissues. INTERPRETATION: A severely compromised metabolism lead to ERK pathway induction, and primes some HCC cells to pro-survival phenotypes upon ERK pathway blockade. Our findings offer novel insights for understanding, predicting and overcoming drug resistance in liver cancer patients. FUND: DFG, BMBF and Sino-German Cooperation Project.

Authors: Z. C. Nwosu, W. Pioronska, N. Battello, A. D. Zimmer, B. Dewidar, M. Han, S. Pereira, B. Blagojevic, D. Castven, V. Charlestin, P. Holenya, J. Lochead, C. De La Torre, N. Gretz, P. Sajjakulnukit, L. Zhang, M. H. Ward, J. U. Marquardt, M. P. di Magliano, C. A. Lyssiotis, J. Sleeman, S. Wolfl, M. P. Ebert, C. Meyer, U. Hofmann, S. Dooley

Date Published: 25th Apr 2020

Publication Type: Not specified

Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers.
LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI)

Abstract (Expand)

BACKGROUND AND AIMS: Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular … carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. APPROACH AND RESULTS: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 x 10(-6) ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 x 10(-4) ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 x 10(-26) ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 x 10(-23) ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (ORallelic , 0.75; 95% CI, 0.64-0.87; P = 1.72 x 10(-4) ). CONCLUSIONS: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.

Authors: F. Stickel, P. Lutz, S. Buch, H. D. Nischalke, I. Silva, V. Rausch, J. Fischer, K. H. Weiss, D. Gotthardt, J. Rosendahl, A. Marot, M. Elamly, M. Krawczyk, M. Casper, F. Lammert, T. W. M. Buckley, A. McQuillin, U. Spengler, F. Eyer, A. Vogel, S. Marhenke, J. von Felden, H. Wege, R. Sharma, S. Atkinson, A. Franke, S. Nehring, V. Moser, C. Schafmayer, L. Spahr, C. Lackner, R. E. Stauber, A. Canbay, A. Link, L. Valenti, J. I. Grove, G. P. Aithal, J. U. Marquardt, W. Fateen, S. Zopf, J. F. Dufour, J. Trebicka, C. Datz, P. Deltenre, S. Mueller, T. Berg, J. Hampe, M. Y. Morgan

Date Published: 21st Oct 2019

Publication Type: Journal

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