Subgroup: Tumor mouse models

Our subgroup is involved in characterization of various mouse models of gastrointestinal diseases/cancers and cancer associated inflammation. Our research focusses on both the physiological aspects of diseases (in vivo models), as well as on the regulation of signaling networks underpinning the (patho)-physiology. The group of Professor Seufferlein has a longstanding track record in the identification and functional characterization of intracellular protein kinases, such as PKDs and the tyrosine kinase TNK1 [1-7] that regulate cell proliferation, survival, motility, cancer associated angiogenesis along with inflammation in gastrointestinal tract. Our subgroup focuses on the functional  characterization of these kinases in the context of the intact organism using genetically engineered mouse models.

Projects

Protein Kinase D enzymes in pancreatic cancer development, progression and invasion

Aberrant expression of the members of the Protein kinase D family is associated with hallmarks of cancer, such as deregulated cell proliferation, survival, motility and epithelial mesenchymal transition. PKDs also regulate the tumor microenvironment, e.g. angiogenesis and inflammation [8-12]. We are investigating specific phenotypes of PKD isoforms in respect to pancreatic cancer development, progression, and invasion using an in vivo model of pancreatic cancer as an experimental platform. This model mimics the disease as it reproduces genetic alterations, such as activating mutation in Kras implicated in the progression of pancreatic ductal adenocarcinoma. Mice display a spectrum of pathologic changes, from pancreatic intraepithelial neoplasia to lesions that progress histologically culminating in fully invasive and metastatic disease. In this system we are characterizing the impact of a loss of PKD1 and PKD2 expression in respect to the cellular and molecular pathology of pancreatic neoplasia and cancer (Fig. 1).

Results:

Our data suggest that loss of PKD1 contributes to very early events that alter pancreatic cellular plasticity. The loss of PKD1 in pancreatic acinar cells synergizes with oncogenic Kras to drive differentiation and reprogramming of pancreatic epithelial cells, which is believed to be one of the earliest events to initiate pancreatic cancer. In addition, loss of PKD1 in a KrasG12D background results in earlier appearance of suppressive cellular elements of the host immune system during pancreatic tumorigenesis, which precede and possibly outweigh anti-tumor cellular immunity contributing to disease progression.

TNK1 in differentiation, transformation and regeneration of the intestinal epithelium

his project focuses on the cellular and molecular mechanisms of how the gut functions as the motor behind multiple organ dysfunction [13, 14]. We hypothesize that among the many factors that play an important role in the pathophysiology of multiple organ dysfunction in patients with hemorrhage and trauma, inappropriate induction of apoptosis may be critical. We aim to determine whether trauma related changes in apoptotic frequency are associated with the alteration of the apoptosis-regulating factor TNK1. All elements of the gut (the epithelium, the immune system, and the microbiome) are impacted by a critical illness and can, in turn, trigger a pathologic host response. Because of the complexity of the disorder, we examine the function of TNK1 in the context of the intact organism using various mouse models, such as intestine specific TNK1 knockout mice, a TNK1 gain-of-function mouse model as well as poly-trauma/hemorrhagic shock mouse and septic shock mouse model (Fig. 2).
 

Relevant publications:
  • Azoitei N., Brey A., Busch T., Fulda S., Adler G., Seufferlein T. Thirty-eight-negative kinase 1 (TNK1) facilitates TNFalpha-induced apoptosis by blocking NF-kappaB activation. Oncogene, 2007. 26(45): p. 6536-45.
  • Gu T.L., Cherry J., Tucker M., Wu J., Reeves C., Polakiewicz R.D. Identification of activated Tnk1 kinase in Hodgkin's lymphoma. Leukemia, 2010. 24(4): p. 861-5.
  • Henderson M.C., Gonzales I.M., Arora S., Choudhary A., Trent J.M., Von Hoff D.D., Mousses S., Azorsa D.O. High-throughput RNAi screening identifies a role for TNK1 in growth and survival of pancreatic cancer cells. Mol Cancer Res, 2011. 9(6): p. 724-32.
  • Hoare S., Hoare K., Reinhard M.K., Lee Y.J., Oh S.P., May W.S. Jr. Tnk1/Kos1 knockout mice develop spontaneous tumors. Cancer Res, 2008. 68(21): p. 8723-32.
  • May W.S., Hoare K., Hoare S., Reinhard M.K., Lee Y.J., Oh S.P.Tnk1/Kos1: a novel tumor suppressor. Trans Am Clin Climatol Assoc, 2010. 121: p. 281-92; discussion 292-3.
  • Hoare K., Hoare S., Smith O.M., Kalmaz G., Small D., May W. S. Kos1, a nonreceptor tyrosine kinase that suppresses Ras signaling. Oncogene, 2003. 22(23): p. 3562-77.
  • Hoare S., Hoare K., Reinhard M.K., Flagg T.O., May W.S. Jr. Functional characterization of the murine Tnk1 promoter. Gene, 2009. 444(1-2): p. 1-9.
  • Eiseler T., Döppler H., Yan I.K., Kitatani K., Mizuno K., Storz P. Protein kinase D1 regulates cofilin-mediated F-actin reorganization and cell motility through slingshot. Nat Cell Biol. 2009 May;11(5):545-56. doi: 10.1038/ncb1861. Epub 2009 Mar 29.
  • Azoitei N., Pusapati G.V., Kleger A., Möller P., Küfer R., Genze F., Wagner M., van Lint J., Carmeliet P., Adler G., Seufferlein T. Protein kinase D2 is a crucial regulator of tumor cell-endothelial cell communication in gastrointestinal tumors. GUT (2010), 59(10): 1316-30.
  • Wille C., Köhler C., Armacki M., Jamali A., Gössele U., Pfizenmaier K., Seufferlein T., Eiseler T. Protein kinase D2 induces invasion of pancreatic cancer cells by regulating matrix metalloproteinases. Mol Biol Cell. 2014 Feb;25(3):324-36. doi: 10.1091/mbc.E13-06-0334. Epub 2013 Dec 11.
  • Wille C., Seufferlein T., Eiseler T. Protein Kinase D family kinases: roads start to segregate. Bioarchitecture. 2014;4(3):111-5. doi: 10.4161/bioa.29273. Epub 2014 May 21.
  • Armacki M., Joodi G., Nimmagadda S.C., de Kimpe L., Pusapati G. V., Vandoninck S., Van Lint J., Illing A. and Seufferlein T. A novel splice variant of calcium and integrin-binding protein 1 mediates protein kinase D2-stimulated tumour growth by regulating angiogenesis. Oncogene (2014) 33: 1167-1180.
  • Deitch E.A. The role of intestinal barrier failure and bacterial translocation in the development of systemic infection and multiple organ failure. Arch Surg, 1990. 125(3): p. 403-4.
  • Moore F.A. The role of the gastrointestinal tract in postinjury multiple organ failure. Am J Surg, 1999. 178(6): p. 449 53.

Staff

Postdoc / Principal Investigator

Profilbild von Dr. med. Milena Armacki

Dr. med. Milena Armacki

Current group members

Lucas Bettac

Ann Elwanger

Claudia Längle

Research Technician

Beate Knobel

Cooperation Partners

  • Prof. Markus Huber-Lang, Clinical and Experimental Trauma Immunology, Ulm
  • Prof. Eckhard Wolf, Gene Center, München
  • PD Dr. Marlon Schneider, Gene Center, München
  • Prof. Hans Kestler, Medical Systems Biology, Ulm
  • Prof. Stefan Reber,  Molecular Psychosomatic Medicine, Ulm
  • PD.Dr. Konrad Steinestel, Pathology, University Hospital, Münster.
  • Prof. Andrea Tannapfel, Pathology, Ruhr-University-Bochum.
  • Prof. Paul Walter,  Electron Microscopy Facility, Ulm
  • Prof. Cornelia Brunner, Dep. of Oto-Rhino-Laryngology, University of Ulm

Selected publications

  • Wille C., Köhler C., Armacki M., Jamali A., Gössele U., Pfizenmaier K., Seufferlein T., Eiseler T. Protein kinase D2 induces invasion of pancreatic cancer cells by regulating matrix metalloproteinases. Mol Biol Cell. 2014 Feb;25(3):324-36. doi: 10.1091/mbc.E13-06-0334. Epub 2013 Dec 11.
  • Armacki M., Joodi G., Nimmagadda S.C., de Kimpe L., Pusapati G.V., Vandoninck S., Van Lint J., Illing A., Seufferlein T. A novel splice variant of calcium and integrin-binding protein 1 mediates protein kinase D2-stimulated tumour growth by regulating angiogenesis.Oncogene. 2014 Feb 27;33(9):1167-80. doi: 10.1038/onc.2013.43.
  • Armacki M., Busch T., Eiseler T., Joodi G., Temme C., Jansen J., von Wichert g., Omary M. B., Spatz J. and Seufferlein T. Keratin 8 phosphorylation regulates keratin reorgantion and migration of epithelial tumor cells. J Cell Sci (2012) 125(Pt 9): 2148-2159.
  • Pusapati G. V., Krndija D., Armacki M., von Wichert G., von Blume J., Malhotra V., Adler G. and Seufferlein T. Role of the second cysteine-rich domain and Pro275 in protein kinase D2 interaction with ADP-ribosylation factor 1, trans-Golgi network recruitment, and protein transport. Mol Biol Cell (2012) 21(6): 1011-1022.
  • Kleger A., Loebnitz C., Pusapati G.V., Armacki M., Müller M., Tümpel S., Illing A., Hartmann D., Brunner C., Liebau S., Rudolph K.L., Adler G., Seufferlein T. Protein kinase D2 is an essential regulator of murine myoblast differentiation. PLoS One. 2011 Jan 27;6(1):e14599. doi: 10.1371/journal.pone.0014599.
  • De Kimpe L., Janssens K., Derua R., Armacki M., Goicoechea S., Otey C., Waelkens E., Vandoninck S., Vandenheede J.R., Seufferlein T., Van Lint J. Characterization of cortactin as an in vivo protein kinase D substrate: interdependence of sites and potentiation by Src. Cell Signal. 2009 Feb;21(2):253-63. doi: 10.1016/j.cellsig.2008.10.015.