Pancreatic development, stem cell differentiation and Cancer

AG Prof. Dr. Kleger

 

Our laboratory aims for a better understanding of the biology, pathology, and clinical utility of pancreatic development, inherited pancreatic syndromes and pancreatic cancer using human and murine pluripotent stem cells and genetically engineered mouse models (GEM). We focus our studies on pancreas development and on common mechanisms of pluripotent stem cell biology and cancer. Our goals are to define principles of how pluripotent stem cells commit toward the mature pancreatic lineages using the progeny as a patient-specific disease model.

Thereby, we have built up resources for pancreatic disease modelling such as an iPS cell bank including a series of inherited pancreatic disease and various genetically engineered mouse strains lacking DNA damage repair genes in the context of Kras driven carcinogenesis. The latter aim to mimic certain human subtypes of pancreatic ductal adenocarcinoma (PDAC).  

Profilbild von apl. Prof. Dr. rer. med. Alexander Kleger

apl. Prof. Dr. rer. med. Alexander Kleger

Oberarzt, Leiter Schwerpunkt Pankreatologie

Alexander Kleger has been trained as an MD and graduated in 2006. He obtained a doctoral grade in biomedical science “summa cum laude” and habilitated in 2013 with his work „Stem cell differentiation and cellular reprogramming as clinically relevant model systems“ after a postdoctoral fellowship at the Institute for Molecular Medicine and Max-Planck-Research Group for Stem Cell Aging.

His laboratory implements human and mouse pluripotent stem cells and genetically engineered mouse models to study pancreatic development, inherited pancreatic syndromes and pancreatic cancer. His research received numerous awards such as the Adolf-Kußmaul Prize, the prestigious UEGW Top Abstract Award and most recently the rising star award of the UEG. He is a former and current Else-Kröner Fresenius fellow.

For more details click on his curriculum vitae.

 

 

Research Groups and People

News

Alexander Kleger honored by UEG Rising Star 2018.

https://www.dgvs.de/dgvs-im-blick/dgvs-preistraeger/rising-star-2018/

Annual Meeting of the German Pancreatic Club in Ulm.

http://www.dpc-kongress.de/

New publication Hohwieler et al.
“Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling”
at the Cover of GUT.

Dr. med. Lukas Perkhofer receives prestigious Martin Gülzow-Award at the DGVS.

Für grundlegende und richtungsweisende Arbeiten im Bereich der klinischen Gastroenterologie vergibt die Fachgesellschaft den Martin Gülzow-Preis. 2017 geht dieser an Dr. Lukas Perkhofer aus Ulm seine Arbeit mit dem Titel „Der Verlust von ATM generiert genomische Instabilität und ermöglicht neue therapeutische Strategien des duktalen Pankreaskarzinoms“. Die Vergabe des Preises erfolgt mit freundlicher Unterstützung der MSD SHARP & DOHME GMBH.

 

Dr. rer. nat. Meike Hohwieler receives Otto-Porges Preis at 72. Jahrestagung der Deutschen Gesellschaft für Verdauungs- und Stoffwechselkrankheiten (DGVS).

www.viszeralmedizin.com/auszeichnungen-2017/abstractpreise/

Tailored therapies for ATM-mutated cancer, Perkhofer et al.  “ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage” goes online.


Kleger lab receives 3 Travel Grants 1.000 € for abstracts of Dr. rer. nat. Meike Hohwieler, Markus Breunig
and Dr. med. Lukas Perkohofer.

Sandra Heller receives the 10.000 £ Lush Prize.

http://lushprize.org/de/preistraeger-2017/

Animal-free diabetes modelling on an iPSC chip platform.

In 2015, the German federal institute for risk assessment granted animal studies with a total number of 25K mice for diabetes research. In order to substantially reduce the number of mice we are currently missing an in vitro cell system recapitulating the function of pancreatic insulin-producing islets. Therefore, we plan to establish a chip platform to culture thousands of micro-islets that can be stimulated with glucose and drug components. Finally, we will be able to analyze different secreted proteins from these treated insulin-producing islets.

For the production of human micro-islets, we will differentiate human embryonic stem cells (ESC) or human induced pluripotent stem cells (iPSC) generated from patient tissue into pancreatic hormone-producing cells according to a recently published differentiation protocol. Then, we will optimize the formation of micro-islets with agarose micro-well arrays by testing the number of required cells in the array, the duration of the formation process, and viability of the micro-islets in the print chip platform.

Finally, to investigate insulin and glucagon secretion of human micro-islets under variable conditions we plan to apply the chip technology. This will help to replace animal testing in diabetes research and facilitate a faster and more physiological and personalized analysis.

 

Markus Breunig receives Poster Prize when attending the Stem Cell Society Singapore Meeting.

http://www.stemcell.org.sg/symposia/

 

Liebau and Kleger lab dissect the process of reprogramming toward induced pluripotency.

www.ncbi.nlm.nih.gov/pubmed/29185460

Dr. rer. nat. Meike Hohwieler receives best poster ward at the 4th Annual Conference of the GSCN in Hannover.

 

 

Publications

- Genetic Biopsy for Prediction of Surveillance Intervals after Endoscopic Resection of Colonic Polyps: Results of the GENESIS Study. Berger AW, Raedler K, Langner C, Ludwig L, Dikopoulos N, Becker KF, Slotta-Huspenina J, Quante M, Schwerdel D, Perkhofer L, Kleger A, Zizer E, Oswald F, Seufferlein T, Meining A. United European Gastroenterol J. 2018 Mar;6(2):290-299.

- Targeted deep sequencing of circulating tumor DNA in metastatic pancreatic cancer. Berger A, Schwerdel D, Ettrich T, Hann A, Schmidt S, Kleger A, Marienfeld R, Seufferlein T. Oncotarget, 2017 Dec 16;9(2):2076-2085.

- Reprogramming to pluripotency does not require transition through a primitive streak-like state Raab S, Klingenstein M, Möller A, Illing A, Tosic J, Breunig M, Kuales G, Linta L, Seufferlein T, Arnold SJ, Kleger A #, Liebau S #, Sci Rep., in press, # corresponding authors.

- Expanding the mutational spectrum in Johanson-Blizzard syndrome: identification of whole exon deletions and duplications in the UBR1 gene by multiplex ligation-dependent probe amplification analysis. Sukalo M, Schäflein E, Schanze I, Everman DB, Rezaei N, Argente J, Lorda-Sanchez I, Deshpande C, Takahashi T, Kleger A, Zenker M. Mol Genet Genomic Med. 2017 Nov;5(6):774-780.

- ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage. Perkhofer L, Schmitt A, Romero Carrasco MC, Ihle M, Hampp S, Ruess DA, Hessmann E, Russell R, Lechel A, Azoitei N, Lin Q, Liebau S, Hohwieler M, Bohnenberger H, Lesina M, Algül H, Gieldon L, Schröck E, Gaedcke J, Wagner M, Wiesmüller L, Sipos B, Seufferlein T, Reinhardt HC, Frappart PO, Kleger A. Cancer Res. 2017 Oct 15;77(20):5576-5590. doi: 10.1158/0008-5472.

- Hsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells.Ernst K, Schmid J, Beck M, Hägele M, Hohwieler M, Hauff P, Ückert AK, Anastasia A, Fauler M, Jank T, Aktories K, Popoff MR, Schiene-Fischer C, Kleger A, Müller M, Frick M, Barth H. Sci Rep. 2017 Jun 2;7(1):2724. doi: 10.1038/s41598-017-02882-y.

- Treatment monitoring in metastatic colorectal cancer patients by quantification and KRAS genotyping of circulating cell-free DNA. Berger AW, Schwerdel D, Welz H, Marienfeld R, Schmidt SA, Kleger A, Ettrich TJ, Seufferlein T. PLoS One. 2017 Mar 22;12(3):e0174308. doi: 10.1371/journal.pone.0174308.

- Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling. Hohwieler M, Illing A, Hermann PC, Mayer T, Stockmann M, Perkhofer L, Eiseler T, Antony JS, Müller M, Renz S, Kuo CC, Lin Q, Sendler M, Breunig M, Kleiderman SM, Lechel A, Zenker M, Leichsenring M, Rosendahl J, Zenke M, Sainz B Jr, Mayerle J, Costa IG, Seufferlein T, Kormann M, Wagner M, Liebau S, Kleger A. Gut. 2016 Sep 15. pii: gutjnl-2016-312423.

- Tbx3 fosters pancreatic cancer growth by increased angiogenesis and activin/nodal-dependent induction of stemness. Perkhofer L, Walter K, Costa IG, Carrasco MC, Eiseler T, Hafner S, Genze F, Zenke M, Bergmann W, Illing A, Hohwieler M, Köhntop R, Lin Q, Holzmann KH, Seufferlein T, Wagner M, Liebau S, Hermann PC #, Kleger A #, Müller M. Stem Cell Res. 2016 Sep;17(2):367-378. doi: 10.1016/j.scr.2016.08.007. # corresponding authors.

- Open Surgical versus Minimal Invasive Necrosectomy of the Pancreas-A Retrospective Multicenter Analysis of the German Pancreatitis Study Group. Rasch S, Phillip V, Reichel S, Rau B, Zapf C, Rosendahl J, Halm U, Zachäus M, Müller M, Kleger A, Neesse A, Hampe J, Ellrichmann M, Rückert F, Strauß P, Arlt A, Ellenrieder V, Gress TM, Hartwig W, Klar E, Mössner J, Post S, Schmid RM, Seufferlein T, Siech M, Werner J, Will U, Algül H. PLoS One. 2016 Sep 26;11(9):e0163651. doi: 10.1371/journal.pone.0163651. eCollection 2016.

- Circulating cell-free DNA is a reliable tool to detect hot spot mutations in intraductal papillary mucinous neoplasms of the pancreas. Berger A, Schwerdel D, Costa IG, Hackert T, Strobel O, Lam S, Barth T, Schröppel B, Meining A, Büchler MW, Zenke M, Hermann PC, Seufferlein T #, Kleger A #. Gastroenterology, 2016, Aug;151(2):267-70. # corresponding authors.

- Cortactin is a scaffolding platform for the E-cadherin adhesion complex and is regulated by protein kinase D1 phosphorylation. Sroka R, Van Lint J, Katz SF, Schneider MR, Kleger A, Paschke S, Seufferlein T, Eiseler T. J Cell Sci. 2016 Jun 15;129(12):2416-29. doi: 10.1242/jcs.184721. Epub 2016 May 13.

- „Miniguts" from plucked human hair meet Crohn´s disease. Hohwieler M1, Renz S, Liebau S, Lin Q, Lechel A, Klaus J, Perkhofer L, Zenke M, Seufferlein T, Illing A, Müller M, Kleger A. Z Gastroenterol, 2016, 2016 Aug;54(8):748-59.

- A dynamic role of Tbx3 in the pluripotency circuitry. Russell R, Ilg M, Lin Q, Wu G, Linta L, Hohwieler M, Lechel A, Bergmann W, Kumar PP, Klingenstein M, Sakk O, Raab S, Moon A, Zenke M, Seufferlein T, Schöler H, Illing A, Liebau S, Kleger A. Stem Cell Reports, 2015 Dec 8;5(6):1155-70.

- TBX3 knockdown decreases reprogramming efficiency of human cells. Klingenstein M, Raab S, Achberger K, Kleger A #, Liebau S #, Linta L #. Stem Cells Int., 2016;2016:6759343. # corresponding authors.

-Loss of ATM accelerates pancreatic cancer formation and Epithelial-Mesenchymal-Transition. Russell R, Perkhofer L, Liebau S, Lin Q, Lechel A, Feld FM, Zenke M, Illing A, Hartmann D, von Figura G, Weissinger SE, Rudolph KL, Möller P, Lennerz JK, Seufferlein T, Wagner M #, Kleger A #. Nature Communications, in press. # corresponding authors.

- A time frame permissive for Protein Kinase D2 activity to direct angiogenesis in mouse embryonic stem cells. Müller M, Schröer S, Azoitei N, Eiseler T, Bergmann W, Köhntop R, Lin L, Zenke M, Genze F, Weidgang C, Seufferlein T, Liebau S #, Kleger A #. Scientific Reports, 2015 Jul 7;5:11742. doi: 10.1038/srep11742. # corresponding authors.

- Self-expandable metal stents for persisting esophageal variceal bleeding after band ligation or injection-therapy: A retrospective study. Martin Müller, Thomas Seufferlein, Martin Wagner, Alexander Kleger. PLoS One, PLoS One. 2015 Jun 22;10(6):e0126525.

- TBX3 Directs Cell-Fate Decision toward Mesendoderm. Weidgang CE *, Russell R *, Tata PR *, Kühl SJ, Illing A, Müller M, Lin Q, Brunner C, Boeckers TM, Bauer B, Kartikasari AER, Guo Y, Radenz M, Bernemann C, Weiß M, Seufferlein S, Zenke M, Iacovino M, Kyba M, Schöler HR, Kühl M, Liebau S #, and Kleger A #. Stem Cell Reports, ISSCR and Cell Press, 2013 Aug 29;1(3):248-65. * equal contribution. # corresponding authors.

- Absence of FLICE-Inhibitory Protein Is a Novel Independent Prognostic Marker for Very Short Survival in Pancreatic Ductal Adenocarcinoma. Schmid SJ *, Glatzel MC*, Welke C, Kornmann M, Kleger A, Barth TFE, Fulda S, Lennerz JK, and Möller. Pancreas, 2013, Oct;42(7):1114-9. * equal contribution.

- Definitive Endoderm Formation from Plucked Human Hair-Derived Induced Pluripotent Stem Cells and SK Channel Regulation. Illing A *, Stockmann M *, Telugu NS, Linta L, Russell R, Müller M, Seufferlein T, Liebau S #, Kleger A #. Stem Cells Int, 2013;2013:360573. * equal contribution. # corresponding authors.

- Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed hiPSCs to Differentiated Neuronal and Cardiac Progeny. Linta L, Stockmann M, Lin Q, Lechel A, Proepper Ch, Boeckers TM, Kleger A #, Liebau L #. Stem Cells Int, 2013, 2013:784629. # corresponding authors.

- Calcium activated potassium channel expression during human iPS cell-derived neurogenesis. Linta L, Boeckers TM, Kleger A #, Liebau S #. Ann Anat. 2013 Mar 28. # corresponding authors.

- Increased Reprogramming Capacity of Mouse Liver Progenitor Cells, Compared With Differentiated Liver Cells, Requires the BAF Complex. Kleger A * #, Mahaddalkar P *, Katz SF, Lechel A, Ju JY, Loya K, Lin Q, Hartmann D, Liebau S, Kraus J, Cantz T, Kestler HA, Zaehres H, Schöler H, Rudolph KL #. Gastroenterology. 2012 Apr;142(4):907-17. * equal contribution. # corresponding authors.

- Developmental and functional nature of human iPSC derived motoneurons. Stockmann M, Linta L, Föhr KJ, Boeckers A, Ludolph AC, Kuh GF, Udvardi PT, Proepper C, Storch A, Kleger A, Liebau S, Boeckers TM. Stem Cell Reviews and Reports, 2011 Nov 3. [Epub ahead of print].

- Ca2+-activated K+-Channels - New Tools to induce Cardiac Commitment from Pluripotent Stem Cells in Mice and Men. Müller M *, Stockmann M *, Malan D, Wolheim A, Tischendorf M, Linta L, Katz SF, Lin Q, Latz S, Brunner C, Wobus AM, Zenke M, Wartenberg M, Boeckers TB, von Wichert G, Fleischmann BF, Liebau S #, Kleger A #. Stem Cell Reviews and Reports, 2012 Sep;8(3):720-40. * equal contribution. # corresponding authors.

- An inducible expression system of the calcium activated potassium channel 4 to study the differential impact on embryonic stem cells. Liebau S, Tischendorf M, Ansorge D, Linta L, Stockmann M, Weidgang C, Iacovino M, Boeckers T, Kyba M, Kleger A. Stem Cells Int. 2011;2011:456815.

- Protein kinase D2 is a novel regulator of glioblastoma growth and tumor formation. Azoitei N *, Kleger A *, Schoo N, Thal D, Brunner C, Pusapati GV, Filatova A, Genze F, Möller P, Acker T, Kuefer R, Van Lint J, Baust H, Adler G, Seufferlein T. *equal contribution. Neuro Oncol. 2011 Jul;13(7):710-24. * equal contribution.

- Rat embryonic fibroblasts improve reprogramming of human keratinocytes into induced pluripotent stem cells. Linta L, Stockmann M, Böckers A, Böckers TM, Kleger A # and Liebau S #. Stem Cells Dev. 2012 Apr 10;21(6):965-76. [Epub 2011 Aug 5]. # corresponding authors.

- Telomerase gene mutations are associated with cirrhosis formation. Hartmann D, Srivastava U, Thaler M, Kleinhans KN, N'kontchou G, Scheffold A, Bauer K, Kratzer RF, Kloos N, Katz SF, Song Z, Begus-Nahrmann Y, Kleger A, von Figura G, Strnad P, Lechel A, Günes C, Potthoff A, Deterding K, Wedemeyer H, Ju Z, Song G, Xiao F, Gillen S, Schrezenmeier H, Mertens T, Ziol M, Friess H, Jarek M, Manns MP, Beaugrand M, Rudolph KL. Hepatology. 2011 May;53(5):1608-17.

- An SK3 Channel/nWASP/Abi-1 complex is involved in early neurogenesis. Liebau S, Steinestel J, Linta L, Kleger A, Storch A, Schoen M, Steinestel K, Proepper C, Bockmann J, Schmeisser MJ, Boeckers TM. PLoS One. 2011 Mar;6(3):e14599.

- Regeneration of the exocrine pancreas is delayed in telomere-dysfunctional mice. Figura G, Wagner M, Nalapareddy K, Hartmann D, Kleger A, Adler G, Rudolph KL. PLoS One. 2011 Feb 22;6(2):e17122.

- Protein kinase D2 is an essential regulator of murine myoblast differentiation. Kleger A *, Loebnitz C *, Pusapati GV, Müller M, Tümpel S, Illing A, Hartmann D, Brunner C, Liebau S, Adler G, Seufferlein T. PLoS One. 2011 Jan 27;6(1):e14599. * equal contribution.

- Modulation of calcium-activated potassium channels induces cardiogenesis of pluripotent stem cells and enrichment of pacemaker-like cells. Kleger A, Seufferlein T, Malan D, Tischendorf M, Storch A, Wolheim A, Protze S, Porzner M, Proepper C, Brunner C, Katz SF, Pusapati GV, Bullinger L, Köhntopp R, Giehl K, Spyrantis A, Wittekindt O, Lin Q, Zenke M, Fleischmann BK, Wartenberg M, Wobus AM, Boeckers TM and Liebau S. Circulation. 2010 Nov 2;122(18):1823-36.

- The bioactive lipid sphingosylphosphorylcholine induces differentiation of mouse embryonic stem cells and human promyelocytic leukaemia cells. Kleger A, Busch T, Liebau S, Prelle K, Paschke S, Beil M, Rolletschek A, Wobus AM, Wolf E, Adler G, Seufferlein T. Cell Signal. 2007 Feb;19(2):367-77.

- Mesodermal cell types induce neurogenesis from adult human hippocampal progenitor cells. Herrmann A, Maisel M, Liebau S, Gerlach M, Kleger A, Schwarz J, Kim KS, Antoniadis G, Lerche H, Storch A. J Neurochem. 2006; 98 (2): 629-40.

- An exceptional cause of epigastric pain. Schulte-Kemna L, Kornmann M, Kleger A. Gastroenterology, 2016 Jun;150(7):e1-e2. doi: 10.1053/j.gastro.2016.02.002.

- A rare cause of upper GI bleeding and wasting disease. van Erp RJ, Schröppel B, Barth TF, Seufferlein T, Schmidt SA, Meining A, Kleger A. GUT. 2016 May;65(5):787, 881. doi: 10.1136/gutjnl-2015-310404.

- Case report: Fecal transplantation therapy in refractory clostridium difficile colitis. Kleger A, Schnell J, Essig A, Wagner M, Bommer M, Seufferlein T, Härter G: Dtsch Arztebl Int. 2013 Feb;110(7):108.

- First reported case of disease: Peliosis hepatis as cardinal symptom of Hodgkin's lymphoma. Kleger A #, Bommer M, Kunze M, Klaus J, Leithaeuser F, Wegener M, Adler G, Dikopoulos N. Oncologist. 2009 Nov;14(11):1088-94. # corresponding author.

 

 

Join our lab

The Kleger lab continuously offers MD positions for performing full-time research.
We usually apply for fellowships in organised programmes such as
http://www.uni-ulm.de/einrichtungen/mm/phdprogramme/expmedizin/ or
https://www.uni-ulm.de/med/research-training-group-2254-heterogeneity-and-evolution-in-solid-tumours-heist/

In case you are interested please send your application documents to
alexander.kleger@uni-ulm.de or pierre-olivier.frappart@uni-ulm.de.

The Kleger lab continuously offers Master and Bachelor positions.
In case you are interested please send your application documents to
alexander.kleger@uni-ulm.de or pierre-olivier.frappart@uni-ulm.de.

There are currently no in house funded positions available.
In case you are supported by a fellowship feel free to send your CV and full application documents to
alexander.kleger@uni-ulm.de or pierre-olivier.frappart@uni-ulm.de

 

 

Funding

 

 

Gallery

 

 

Good Old Friends

  • Dr. Ronan Russell
  • Dr. Anett Illing
  • Wendy Bergmann
  • Markus Ilg
  • Stefanie Fischer
  • Clair Weidgang
  • Christiane Loebnitz
  • Michael Tischendorf