Entwicklung und Anwendung analytischer Methoden für die metabolische Zellanalyse unter physiologischen und pathologischen Bedingungen

• Antragstellerinnen / Antragsteller: Privatdozentin Dr. Katja Dettmer-Wilde; Professor Dr. Wolfram Gronwald; Professor Dr. Peter Oefner, seit 1/2018; Professor Dr. Rainer Spang
• Fachliche Zuordnung: Hämatologie, Onkologie
• Förderung: Förderung von 2011 bis 2020
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 190230491

• Erstellungsjahr: 2019

Zusammenfassung der Projektergebnisse

Over the entire project duration of the KFO, we have significantly extended our method portfolio to comprehensively analyze tumor metabolism and its role in immune escape and tumor progression. This includes among others the analysis of tryptophan metabolites, 2-HG, total GSH, and 13C tracer analysis by hyphenated mass spectrometry or non-uniform sampling by NMR. The analysis of metabolites was complemented by proteomics investigations implementing for example the newly available “SWATH-mass spectrometry” technique. In addition to the instrumental analysis, we optimized and expanded our data analysis strategies, e.g. data normalization, causal modelling, etc. Overall, investigators from the core project contributed with support from the KFO to 40 publications in total over the two funding periods not considering publications that are currently in the review/revision stage.

Projektbezogene Publikationen (Auswahl)

• (2012) Performance evaluation of algorithms for the classification of metabolic 1H-NMR fingerprints. Journal of Proteome Research 11:6242-6251
  Hochrein J, Klein MS, Zacharias HU, Li J, Wijffels G, Schirra HJ, Spang R, Oefner PJ, Gronwald W
  (Siehe online unter https://doi.org/10.1021/pr3009034)
• (2013) Diclofenac inhibits lactate formation and efficiently counteracts local immune suppression in a murine glioma model. Int. J. Cancer 132:843-853
  Chirasani SR, Leukel P, Gottfried E, Hochrein J, Stadler K, Neumann B, Oefner PJ, Gronwald W, Bogdahn U, Hau P, Kreutz M, Grauer OM
  (Siehe online unter https://doi.org/10.1002/ijc.27712)
• (2013) Distinct metabolic differences between various human cancer and primary cells. Electrophoresis 34(19):2836–2847
  Dettmer K, Vogl FC, Ritter AP, Zhu W, Nürnberger N, Kreutz M, Oefner PJ, Gronwald W, Gottfried E
  (Siehe online unter https://doi.org/10.1002/elps.201300228)
• (2013) New aspects of an old drug - diclofenac targets MYC and glucose metabolism in tumor cells. PLoS One 8(7):e66987
  Gottfried E, Lang SA, Renner K, Bosserhoff A, Gronwald W, Rehli M, Einhell S, Gedig I, Singer K, Seilbeck A, Mackensen A, Grauer O, Hau P, Dettmer K, Andreesen R, Oefner PJ, Kreutz M
  (Siehe online unter https://doi.org/10.1371/journal.pone.0066987)
• (2014) CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs. Blood 124(5):750–760
  Jitschin R, Braun M, Büttner M, Dettmer-Wilde K, Bricks J, Berger J, Eckart MJ, Krause SW, Oefner PJ, Le Blanc K, Mackensen A, Mougiakakos D
  (Siehe online unter https://doi.org/10.1182/blood-2013-12-546416)
• (2014) Collagen XVI induces expression of MMP9 via modulation of AP-1 transcription factors and facilitates invasion of oral squamous cell carcinoma. PLoS ONE 9(1):e86777
  Bedal KB, Grässel S, Oefner PJ, Reinders J, Reichert TE, Bauer R
  (Siehe online unter https://doi.org/10.1371/journal.pone.0086777)
• (2014) Continuous water infusion enhances atmospheric pressure chemical ionization of methyl chloroformate derivatives in gas chromatography coupled to time-of-flight mass spectrometry-based metabolomics. Analytical Chemistry 86(18):9186-9195
  Wachsmuth CJ, Dettmer K, Lang SA, Mycielska ME, Oefner PJ
  (Siehe online unter https://doi.org/10.1021/ac502133r)
• (2015) Causal Modeling of Cancer-Stromal Communication Identifies PAPPA as a Novel Stroma-Secreted Factor Activating NFκB Signaling in Hepatocellular Carcinoma. PLoS Computational Biology 11(5):e1004293
  Engelmann JC, Amann T, Ott-Rötzer B, Nützel M, Reinders Y, Reinders J, Thasler WE, Kristl T, Teufel A, Huber CG, Oefner PJ, Spang R, Hellerbrand C
  (Siehe online unter https://doi.org/10.1371/journal.pcbi.1004293)
• (2015) Data Normalization of 1H-NMR Metabolite Fingerprinting Datasets in the Presence of Unbalanced Metabolite Regulation. Journal of Proteome Research 14:2897-2905
  Hochrein J, Zacharias HU, Taruttis F, Samol C, Engelmann JC, Spang R, Oefner PJ, Gronwald W
  (Siehe online unter https://doi.org/10.1021/acs.jproteome.5b00192)
• (2015) Enhanced metabolite profiling using a redesigned atmospheric pressure chemical ionization source for gas chromatography coupled to highresolution time-of-flight mass spectrometry. Analytical Bioanalytical Chemistry 407(22): 6669-6680
  Wachsmuth CJ, Hahn TA, Oefner PJ, Dettmer K
  (Siehe online unter https://doi.org/10.1007/s00216-015-8824-x)
• (2016) LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metabolism 24(5):657–671
  Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, Kastenberger M, Bogdan C, Schleicher U, Mackensen A, Ullrich E, Fichtner-Feigl S, Kesselring R, Mack M, Ritter U, Schmid M, Blank C, Dettmer K, Oefner PJ, Hoffmann P, Walenta S, Geissler EK, Pouyssegur J, Villunger A, Steven A, Seliger B, Schreml S, Haferkamp S, Kohl E, Karrer S, Berneburg M, Herr W, Mueller-Klieser W, Renner K, Kreutz M
  (Siehe online unter https://doi.org/10.1016/j.cmet.2016.08.011)
• (2016) Metformin inhibits proliferation and migration of glioblastoma cells independently of TGF-β2. Cell Cycle 15(13):1755-66
  Seliger C, Meyer AL, Renner K, Leidgens V, Moeckel S, Jachnik B, Dettmer K, Tischler U, Gerthofer V, Rauer L, Uhl M, Proescholdt M, Bogdahn U, Riemenschneider MJ, Oefner PJ, Kreutz M, Vollmann- Zwerenz A, Hau P
  (Siehe online unter https://doi.org/10.1080/15384101.2016.1186316)
• (2016) Suppressive effects of tumor cell-derived 5'-deoxy-5'-methylthioadenosine on human T cells. Oncoimmunology 5(8):e1184802
  Henrich FC, Singer K, Poller K, Bernhardt L, Strobl CD, Limm K, Ritter AP, Gottfried E, Völkl S, Jacobs B, Peter K, Mougiakakos D, Dettmer K, Oefner PJ, Bosserhoff AK, Kreutz MP, Aigner M, Mackensen A
  (Siehe online unter https://doi.org/10.1080/2162402X.2016.1184802)
• (2017) Biological and clinical significance of tryptophan-catabolizing enzymes in cutaneous T-cell lymphomas. Oncoimmunology 6(3):e1273310
  Maliniemi P, Laukkanen K, Väkevä L, Dettmer K, Lipsanen T, Jeskanen L, Bessede A, Oefner PJ, Kadin ME, Ranki A
  (Siehe online unter https://doi.org/10.1080/2162402X.2016.1273310)
• (2017) Microbiota disruption induced by early use of broad-spectrum antibiotics is an independent risk factor of outcome after allogeneic stem cell transplantation. Journal of the American Society for Blood and Marrow Transplantation 23(5):845–852
  Weber D, Jenq RR, Peled JU, Taur Y, Hiergeist A, Koestler J, Dettmer K, Weber M, Wolff D, Hahn J, Pamer EG, Herr W, Gessner A, Oefner PJ, van den Brink MRM, Holler E
  (Siehe online unter https://doi.org/10.1016/j.bbmt.2017.02.006)
• (2017) Srebp-controlled glucose metabolism is essential for NK cell functional responses. Nature Immunology 18(11):1197–1206
  Assmann N, O'Brien KL, Donnelly RP, Dyck L, Zaiatz-Bittencourt V, Loftus RM, Heinrich P, Oefner PJ, Lynch L, Gardiner CM, Dettmer K, Finlay DK
  (Siehe online unter https://doi.org/10.1038/ni.3838)
• (2018) D-2-hydroxyglutarate interferes with HIF-1α stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization. Oncoimmunology 7(7):e1445454
  Böttcher M, Renner K, Berger R, Mentz K, Thomas S, Cardenas-Conejo ZE, Dettmer K, Oefner PJ, Mackensen A, Kreutz M, Mougiakakos D (
  (Siehe online unter https://doi.org/10.1080/2162402X.2018.1445454)
• (2018) Double genetic disruption of lactate dehydrogenases A and B is required to ablate the "Warburg effect" restricting tumor growth to oxidative metabolism. The Journal of Biological Chemistry 293(41):15947–15961
  Ždralević M, Brand A, Di Ianni L, Dettmer K, Reinders J, Singer K, Peter K, Schnell A, Bruss C, Decking S, Koehl G, Felipe-Abrio B, Durivault J, Bayer P, Evangelista M, O'Brien T, Oefner PJ, Renner K, Pouysségur J, Kreutz M
  (Siehe online unter https://doi.org/10.1074/jbc.RA118.004180)
• (2018) Polyol pathway links glucose metabolism to the aggressiveness of cancer cells. Cancer Research 78(7):1604-1618
  Schwab A, Siddiqui A, Vazakidou ME, Napoli F, Böttcher M, Menchicchi B, Raza U, Saatci Ö, Krebs AM, Ferrazzi F, Rapa I, Dettmer-Wilde K, Waldner MJ, Ekici AB, Rasheed SAK, Mougiakakos D, Oefner PJ, Sahin O, Volante M, Greten FR, Brabletz T, Ceppi P
  (Siehe online unter https://doi.org/10.1158/0008-5472.CAN-17-2834)
• (2019) D-2-Hydroxyglutarate and L-2-hydroxyglutarate inhibit IL-12 secretion by human monocyte-derived dendritic cells. International Journal of Molecular Sciences 20(3):E742
  Berger RS, Ellmann L, Reinders J, Stempfl T, Oefner PJ, Dettmer K (2019) Degradation of D-2- hydroxyglutarate in the presence of isocitrate dehydrogenase mutation. Scientific Reports, in press Ugele I, Cárdenas-Conejo ZE, Hammon K, Wehrstein M, Bruss C, Peter K, Singer K, Gottfried E, Boesch J, Oefner P, Dettmer K, Renner K, Kreutz M
  (Siehe online unter https://doi.org/10.3390/ijms20030742)