Benutzerspezifische Werkzeuge

Metabolism Unit

KFO252_long

Metabolism Unit

Head: Susan Richter, PhD
Staff: Anastasios Mangelis, MS (PhD Student)

Dr. Richter has a strong interest in the involvement of energy pathways in cancer. The research undertaken within the Metabolism unit has however, wider ramifications beyond cancer since many of the metabolic pathways under study are also relevant to other pathogenic processes, such as inflammation, obesity and diabetes.

Mutations in Krebs cycle related genes have been described in a number of cancers, including renal cell carcinoma, gastrointestinal stromal tumors, gliomas, acute myeloid leukemias, and pheochromocytomas/paragangliomas (PPGLs), and may be drivers of other common types of cancer. Especially in PPGLs, succinate dehydrogenase (SDH) B and fumarate hydratase mutations are associated with malignancy. Dr. Richter demonstrated that PPGLs due to mutations in any of the SDH subunits can be identified by their pathogenically altered metabolite levels, which can also be used to stratify patients for malignant risk. This approach is now being applied to other cancer types, both to identify novel pathogenic mutations and elucidate pathogenic mechanisms. 

The mechanisms linking mutations of genes impacting energy metabolism to cancer are not fully understood, but are believed to involve increased levels of oncometabolites, which can lead to activation of hypoxia pathways via stabilization of HIFs. Thus, the work being carried out by Dr. Richter is closely linked to that of Dr. Qin in her studies of hypoxia linked MYC/MAX pathways.

SDHx_Metabolism

Dr. Richter also enjoys close links with the Mass Spectrometry unit for the profiling of energy pathway metabolites. In particular, advances in mass spectrometry provide the opportunity for extensive profiling and precise quantification of metabolites. One of the most powerful techniques taking advantage of these features is stable isotope metabolic flux analysis (SIMFA). SIMFA enables measurements of rate processes in metabolic systems through introduction of stable isotope labeled substrates. Metabolite measurements followed by computational analysis allow the estimations of fluxes, even in complicated biological systems.

Combined with other omics technologies, SIMFA provides a systems biology approach for investigations of complex networks. Our metabolism unit, standing on the edge of this technology, is applying computational modeling techniques in the field of cancer and adrenal dysfunction. In addition to applications to energy metabolism, another focus concerns the application of SIMFA technology to studies of steroidomic metabolic pathways, these linked to investigations of patients with disorders of adrenal cortical function. Underlying concepts are based on an established background of work involving isotope-dilution techniques to map and quantify rates of catecholamine metabolic pathways, both in model systems and in clinical studies involving patients with cardiac failure and neuroendocrine tumors.  

 

Selected Publications

  1. Rao JU, Engelke UF, Sweep FC, Pacak K, Kusters B, Goudswaard AG, Hermus AR, Mensenkamp AR, Eisenhofer G, Qin N, Richter S, Kunst HP, Timmers HJ, Wevers RA. Genotype-specific differences in the tumor metabolite profile of pheochromocytoma and paraganglioma using untargeted and targeted metabolomics. J Clin Endocrinol Metab. 20i5 “in press”
  2. Richter S, Peitzsch M, Rapizzi E, Lenders JW, Qin N, de Cubas AA, Schiavi F, Rao JU, Beuschlein F, Quinkler M, Timmers HJ, Opocher G, Mannelli M, Pacak K, Robledo M, Eisenhofer G. Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency. J Clin Endocrinol Metab. 2014, 99:3903-11.
  3. Canu L, Rapizzi E, Zampetti B, Fucci R, Nesi G, Richter S, Qin N, Giachè V, Bergamini C, Parenti G, Valeri A, Ercolino T, Eisenhofer G, Mannelli M.  Pitfalls in genetic analysis of pheochromocytomas/paragangliomas-case report. J Clin Endocrinol Metab. 2014, 99: 2321-6
  4. Richter S, Qin N, Pacak K, Eisenhofer G. Role of hypoxia and HIF2α in development of the sympathoadrenal cell lineage and chromaffin cell tumors with distinct catecholamine phenotypic features. Adv Pharmacol. 2013;68:285-317.
  5. Richter S, Morrison S, Connor T, Su J, Print CG, Ronimus RS, McGee SL, Wilson WR. Zinc finger nuclease mediated knockout of ADP-dependent glucokinase in cancer cell lines: effects on cell survival and mitochondrial oxidative metabolism. PLoS One. 2013; 8(6):e65267.