Prostate Cancer (Epi)Genomics and Proteomics

The Genomes of Early Onset Prostate Cancers

Prostate cancer (PCA) is generally considered a tumor of elderly men. However, a small fraction of prostate cancers are diagnosed at the age of 50 years or less. A better understanding of these tumors is particularly relevant as finding optimal treatment regimens is most critical in young cancer patients.

In the framework of the ICGC-consortium "The Genomes of Early Onset Prostate Cancers", the genomes and epigenomes of 240 PCA of young men (≤ 50y) were characterized. We sequenced the transcriptomes of 140 mRNA and miRNA samples from these patients.


Publications:

  • Gu L, Frommel S, Oakes CC, Simon R, Grupp K, Gerig C, Bär D, Robinson M, Baer C, Weiss M, Gu Z, Kuner R, Sültmann H, Borsig L, Yaspo ML, Brors B, Korbel J, Schlomm T, Sauter G, Eils R, Plass C, Santoro R. TIP5/BAZ2A Links Polycomb Repression and Epigenetic Remodelling with Recurrence in Prostate Cancer. Nature Genetics 47:22-33, 2015
  • Weischenfeldt J, Simon, R, Feuerbach L, Schlangen K, Weichenhan D, Minner S, Wuttig D, Warnatz H-J, Stehr H, Rausch T, Jäger N, Gu L, Bogatyrova O, Claus R, Eils J, Eils R, Gerhäuser C, Huang P-H, Hutter B, Kabbe R, Lawerenz C, Radomski S, Bartholomä C, Fälth M, Gade S, Schmidt M, von Kalle C, Benes V, Stütz AM, Zichner T, Mader M, Amstislavskiy V, Avci M, Lehrach H, Parkhomchuk A, Sultan M, Burkhardt L, Gräfen M, Huland H, Kluth M, Krohn A, Sirma H, Stumm L, Sültmann H, Sauter G, Plass C, Brors B, Yaspo ML, Korbel JO, Schlomm T. Integrative genomic analyses reveal androgen-driven somatic alteration landscape in early-onset prostate cancer. Cancer Cell 23(2):159-170, 2013
  • Sultan M, Dökel S, Amstislavskiy V, Wuttig D, Sültmann H, Lehrach H, Yaspo ML. A Simple Strand-Specific RNA-Seq library preparation protocol combining Illumina TruSeqRNA Sample kit and the dUTP method. Biochemical and Biophysical Research Communications 422(4):643-646, 2012

Cooperations: Div. of Theoretical Bioinformatics and Translational Oncology, DKFZ; Max-Planck-Institute for Molecular Genetics, Berlin

Support: German Federal Ministry for Education and Research (BMBF) in the program for medical genome research, International Cancer Genome Consortium (ICGC).

Systems Biology of Prostate Cancer

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This project applied and integrated high-throughput technologies towards the identification of molecular signatures allowing the stratification of patients who are susceptible to curative treatment of prostate cancer. We made use of the tissue, serum, and urine samples from the Clinic of Urology at Innsbruck University. The established technology platforms of the different partners included genomic, proteomic, and metabolomic technologies and were used to generate molecular signatures for patient diagnosis, patient stratification and the definition of molecular candidate markers for novel therapy approaches.

Selected Publications:

  • Castelo-Branco P, Leão R, Limpan T, Campbell B, Price A, Zhang C, Börno S, Gomes A, Domingos C, Apolonio JD, Coelho H, Bristow RG, Schweiger MR, Hamilton R, Zlotta A, Figueiredo A, Klocker H, Sültmann H, Tabori U. A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer. A retrospective cohort study. Oncotarget 7(36):57726-57736, 2016
  • Kuner R, Fälth M, Chui-Pressinotti N, Brase JC, Balaguer Puig S, Metzger J, Gade S, Schäfer G, Bartsch G, Steiner E, Klocker H, Sültmann H. Maternal Embryonic Leucine Zipper Kinase (MELK) is upregulated in high-grade prostate cancer. J Mol Med 91(2):237-248, 2013
  • Massoner P, Kugler K, Unterberger K, Kuner R, Mueller L, Fälth M, Schäfer G, Seifarth C, Ecker S, Verdorfer I, Graber A, Sültmann H, Klocker H. Gene expression meta-analysis identified transcriptional changes in ERG-rearrangement positive prostate cancer including the regulation of metabolic sensors, such as neuropeptide Y. PLOS ONE 8(2):e55207, 2013
  • Bu H, Bormann S, Schäfer G, Horninger W, Massoner P, Neeb A, Lakshmanan V-K, Maddalo D, Nestl A, Sültmann H, Cato ACB, Klocker H. The anterior gradient 2 gene is overexpressed in prostate cancer and provides detection of prostate tumors in urine sediments. The Prostate 71:575-587, 2010
  • Pressinotti NC, Klocker H, Schäfer G, Luu VD, Ruschhaupt M, Kuner R, Steiner E, Poustka A, Bartsch G, Sültmann H. Differential expression of apoptotic genes PDIA3 and MAP3K5 distinguishes between low-and high-risk prostate cancer. Molecular Cancer 8:130, 2009

Cooperations: Div. of Urology and Uropathology, Innsbruck Medical University; Div. of Vertebrate Genomics, Max-Planck-Institute for Molecular Genetics, Berlin; Hospital for Sick Children, Toronto

Support: Institute for Medical Genome Research and Systems Biology, (IMGuS), Vienna, Austria; Austrian National Foundation; Austria Wirtschaftsservice GmbH.

Genomics and Proteomics of Prostate Cancer

The project aimed at the generation and integration of orthogonal molecular data in order to increase our understanding of processes contributing to prostate cancer progression. Selected genes from these signatures were further characterized in cellular assays using cell lines and RNA interference methodologies. In addition, we developed novel technologies for the detection of prostate cancer markers in patient serum.

Selected Publications
:

  • Pickl JMA, Tichy D, Kuryshev VY, Tolstov Y, Falkenstein M, Schüler J, Reidenbach D, Hotz-Wagenblatt A, Kristiansen G, Roth W, Hadaschik B, Hohenfellner M, Duensing S, Heckmann D, Sültmann H. Ago-RIP-Seq identifies Polycomb repressive complex I member CBX7 as a major target of miR-375 in prostate cancer progression. Oncotarget 7(37):59589-59603, 2016
  • Kacprzyk LA, Laible M, Andrasiuk T, Brase J, Börno ST, Fälth M, Kuner R, Lehrach H, Schweiger MR, Sültmann H. ERG Induces Epigenetic Activation of Tudor Domain-containing Protein 1 (TDRD1) in ERG Rearrangement-positive Prostate Cancer. PLOS ONE 8(3):e59976, 2013
  • Börno ST, Fischer A, Kerick M, Fälth M, Laible M, Brase JC, Kuner R, Dahl A, Grimm C, Isau M, Roehr C, Wunderlich A, Timmermann B, Claus R, Plass C, Graefen M, Simon R, Demichelis F, Rubin MA, Sauter G, Schlomm T, Sültmann H, Lehrach H, Schweiger MR. Increase in genome-wide differential DNA methylation events in TMPRSS2:ERG fusion negative prostate cancers  miRNA-26a hypermethylation. Cancer Discovery 2(11):1024-1035, 2012
  • Ummanni R, Barreto F, Venz S, Scharf C, Barett C, Mannsperger HA, Kuner R, Brase J, Schlomm T, Sauter G, Sültmann H, Korf U, Bokemeyer C, Walther R, Brümmendorf TH, Balabanov S. Peroxiredoxins 3 and 4 are overexpressed in high risk prostate cancer and affect proliferation of prostate cancer cells in vitro. J Proteome Res 11(4):2452-2466, 2012
  • Brase JC, Johannes, M, Mannsperger, H, Fälth, M, Metzger, J, Kacprzyk, LA, Andrasiuk T, Gade S, Meister M, Sauter, G, Simon R, Schlomm T, Beißbarth T, Korf U, Kuner R, Sültmann H. TMPRSS2-ERG specific transcriptional modulation is associated with prostate cancer biomarkers and TGF-beta signaling. BMC Cancer 11(1):507, 2011
  • Brase JC, Johannes M, Schlomm T, Fälth M, Haese A, Steuber T, Beissbarth T, Kuner R, Sültmann H. Circulating miRNA-375 is correlated with tumor progression in prostate cancer. Int. J. Cancer 128(3):608-616, 2011
  • Brase JC, Mannsperger H, Fröhlich H, Gade S, Schmidt C, Wiemann S, Beissbarth T, Schlomm T, Sültmann H, Korf U. Antibody-mediated signal amplification: A method to increase the sensitivity of reverse phase protein arrays. Proteome Science 8(1):36, 2010

Cooperations: Depts. of Urology and Molecular Urooncology at Heidelberg University Medical Center; Div. of Biostatistics, DKFZ; Inst. Of Pathology, University Medicine Mainz; Div. of Vertebrate Genomics, Max-Planck-Institute for Molecular Genetics, Berlin

Support: German Federal Ministry for Education and Research (BMBF) in the program for medical genome research (NGFNplus).

Lung Cancer Translational Genomics

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Lung cancer is the main cause of mortality among all malignancies in western countries. The prognosis of the disease is very poor. Only 12-15% of the patients survive more than 5 years after initial diagnosis of tumors in late stage (III-IV), when often metastases are already manifest. Thus, better diagnostic tools and more efficient and specific therapies are urgently required.

In the past, our projects focused on the identification of DNA and RNA markers for the prognosis of lung cancer in tissues. More recently, we have been analyzing the contribution of genes and miRNAs to resistance against targeted therapies and on the mutation typing and exome sequencing of plasma DNA to monitor tumor progression and therapy.

Selected Publications:

  • Riediger AL, Dietz S, Schirmer U, Meister M, Heinzmann-Groth I, Schneider M, Muley T, Thomas M, Sültmann H. Mutation analysis of circulating plasma DNA to determine response to EGFR tyrosine kinase inhibitor therapy of lung adenocarcinoma patients. Scientific Reports 6:33505, 2016
  • Dietz S, Schirmer U, Mercé C, Kuryshev V, von Bubnoff N, Dahl E, Meister M, Muley T, Thomas M, Sültmann H. Low input whole-exome sequencing to determine the representation of the tumor exome in circulating DNA of non-small cell lung cancer patients. PLOS ONE 11(8):e0161012, 2016
  • Praveen P, Hülsmann H, Sültmann H, Kuner R, Fröhlich H. Cross-talk between AMPK and EGFR dependent Signaling in Non-Small Cell Lung Cancer. Scientific Reports 6:27514, 2016
  • Hülsmann H, Rolff J, Bender C, Jarahian M, Korf U, Herwig R, Fröhlich H, Thomas M, Merk J, Sültmann H, Kuner R. Activation of AMP-activated protein kinase (AMPK) sensitizes lung cancer cells and H1299 xenografts to Erlotinib. Lung Cancer 86(2):151-157, 2014
  • Kaduthanam S, Gade S, Meister M, Brase JC, Johannes M, Dienemann H, Warth A, Schnabel PA, Herth FJ, Sültmann H, Muley T, Kuner R. Serum miR-142-3p is associated with early relapse in operable lung adenocarcinoma patients. Lung Cancer S0169-5002(13):23-28, 2013
  • Kahn N, Meister M, Eberhardt R, Muley T, Schnabel PA, Bender C, Johannes M, Keitel D, Sültmann H, Herth FJF, Kuner R. Early Detection of Lung Cancer by Molecular Markers in Endobronchial Lining Fluid. J Thor Oncol 7(6):1001-1008, 2012

Cooperations: Thoraxklinik Heidelberg; Div. of Vertebrate Genomics, Max-Planck-Institute for Molecular Genetics, Berlin; Dept. of Pathology at Heidelberg University Medical Center; EPO GmbH, Berlin-Buch

Support: German Federal Minstry for Education and Research (BMBF) in the funding programs German Centers for Lung Research (DZL), Medical Systems Biology (PREDICT), and eBio (EPITREAT).

Functional Analysis of Genes in Disease

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We also apply our genomics and proteomics expertise to cooperative projects aiming at the analysis of genes and biological processes in diverse disease backgrounds. Here, we have contributed to the characterization of spatial and molecular heterogeneity of renal cell cancers, to the molecular analysis of exosome contents in mouse models and to the identification of the receptor for Hepatitis B viruses entering mammalian cells.

 

Selected Publications:

  • Hoefflin R, Lahrmann B, Warsow G, Hübschmann D, Spath C, Walter B, Chen X, Hofer L, Macher-Goeppinger S, Tolstov Y, Korzeniewski N, Duensing A, Grüllich C, Jäger D, Perner S, Schönberg G, Nyarangi-Dix J, Isaac S, Hatiboglu G, Teber D, Hadaschik B, Pahernik S, Roth W, Eils R, Schlesner M, Sültmann H, Hohenfellner M, Grabe N, Duensing S. Spatial niche formation but not malignant progression is a driving force for intratumoral heterogeneity. Nature Communications 7:11845, 2016
  • Ridder K, Sevko A, Heide J, Dams M, Rupp A, Macas J, Starmann J, Tjwa M, Plate K, Sültmann H, Altevogt P, Umansky P, Momma S. Myeloid derived suppressor cells are the principal target for tumor-derived microvesicles in vivo. OncoImmunology 4(6):e1008371, 2015
  • Honegger A, Schilling D, Bastian S, Sültmann H, Hoppe-Seyler K, Hoppe-Seyler F. The Effects of the HPV E6/E7 Oncogenes on the Intracellular and Exosomal miRNA Compositions of HPV-positive Tumor Cells. PLOS Pathogens 11(3):e1004712, 2015
  • Ni Y, Lempp FA, Mehrle S, Nkongolo S, Kaufman C, Fälth M, Stindt J, Kubitz R, Sültmann H, Urban S. Hepatitis B virus exploits sodium taurocholate co-transporting polypeptide (NTCP) for entering hepatocytes in a species-specific manner. Gastroenterology 146:1070-1083, 2014
  • Ridder K, Keller S, Dams M, Rupp AK, Schlaudraff J, Del Turco D, Starmann J, Macas J, Depboylu C, Landfried B, Deller T, Plate KH, Höglinger G, Sültmann H, Altevogt P, Momma S. Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation. PLOS Biology 12(6):e1001874, 2014
  • Wittig-Blaich SM, Kacprzyk LA, Eismann T, Bewerunge-Hudler M, Kruse P, Winkler E, Strauss WSL, Hibst R, Steiner R, Schrader M, Mertens D, Sültmann H, Wittig R. Matrix-dependent  regulation of AKT in hepsin-overexpressing PC3 prostate cancer cells. Neoplasia 13(7):579-589, 2011

Cooperations: Depts. of Urology and Molecular Urooncology at Heidelberg University Medical Center; Institute for Neurology (Edinger Institute), Frankfurt; Hepatitis B Research Group, Heidelberg University, Div. Molecular Therapy of Virus-Associated Tumors, DKFZ

Support: DKFZ intramural funding; German Federal Ministry for Education and Research (BMBF) in the German Cancer Consortium (DKTK).

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