AG Armacki: In Vivo and Ex-Vivo Models

Prof Seufferleins´ group  has a longstanding track record in the identification and functional characterization of protein kinases such as PKDs and TNK1 in health and disease. Our subgroup focuses on physiological aspects of diseases modelled in vivo and ex vivo, using genetically engineered mouse models and organoid culture.

Projects

Role of members of Protein Kinase D family 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 tumour microenvironment, e.g. angiogenesis and inflammation. We are defining specific phenotypes of PKD isoforms in respect to pancreatic cancer development, progression, and invasion using in vivo models of pancreatic cancer as an experimental platform. We have developed mouse models with pancreas specific knockout of PKD isoforms and concomitant expression of oncogenic Kras.

Most recently we have shown that PDAC have reduced levels of PRKD1 compared with non-tumor pancreatic tissues. Loss of PRKD1 results in reduced phosphorylation of cortactin in pancreatic cancer cell lines, resulting in increased in F-actin at the plasma membrane and increased release of sEVs, with altered content. These sEVs promote metastasis of xenograft and pancreatic tumors to lung in mice.

The role of the tyrosine kinase TNK1 in differentiation, transformation and regeneration of the intestinal epithelium

Gut is composed of three entities: the epithelium, the mucosal immune system and the commensal flora.  Preservation of the intestinal homeostasis is achieved through a balance of intestinal integrity, anti-inflammatory and inflammatory response and a diverse composition of bacteria. This balance is skewed in sepsis and critical conditions and it results in a breakdown of the alliance between the cost and the bacterial colonizers, resulting in selection of virulent pathogens,  disbiosis and a robust and maladaptive inflammatory and anti-inflammatory response. This feed-forward pathway allows propagation of the disease, worsening of organ dysfunction  and multiple organ dysfunction syndrome (MODS) can occur.

This project focuses on the cellular and molecular underpinnings of how the gut functions as the motor behind multiple organ dysfunction. We have have shed some light on molecular mechanism underpinning intestinal barrier breach in response to stressors/insult. We have shown that TNK1 mediates intestinal barrier breach, hyperpermeability and finally, resulting septic shock and multi-organ dysfunction.

Our group focus is to examine therapeutic potential of TNK1-targeting in the reconstruction of the impaired intestinal barrier. We examine the effect of TNK1 and its targeting on all three components of intestine: the epithelium, microbiota and intestinal immune system.

Staff

Postdoc / Principal Investigator

  • Profilbild von Dr.Hum.Biol. Milena Armacki

    Dr.Hum.Biol. Milena Armacki

    Senior PostDoc, Group Leader "In Vivo and Ex Vivo Models"

    Schwerpunkte

    Mouse models, Ex-vivo models, Microbiota

Current group members

  • Profilbild von Dr.med. Viktoria Hentschel

    Dr.med. Viktoria Hentschel

    Clinician Scientist, Fachärztin für Innere Medizin

    Schwerpunkte

    Organoidbasierte in vitro Modellierung der Darmbarriere

  • Profilbild von Hongxia Li

    Hongxia Li

    PhD Student

    Schwerpunkte

    Microbiota

  • Profilbild von Danhui Zhang

    Danhui Zhang

    PhD Student

    Schwerpunkte

    Exosomes, Murine Models of Pancreatic Cancer

  • Profilbild von Omer Sehic

    Omer Sehic

    MD Doctoral Student

    Schwerpunkte

    Intestinal Organoids

  • Profilbild von Michaela Mahrle

    Michaela Mahrle

    MSc Student

    Schwerpunkte

    Pancreatic Cancer , 3D Culture

  • Profilbild von Melika Rezaei

    Melika Rezaei

    MSc Student

    Schwerpunkte

    Pancreatic Cancer, 3D Culture, Mouse Cohorts Managing

  • Profilbild von Claudia Längle

    Claudia Längle

    Technical Assistant, CTA

    Schwerpunkte

    RNA, PCR, WB

  • Profilbild von Beate Knobel

    Beate Knobel

    Technical Assistant, UTA

    Schwerpunkte

    Tissue Processing, Immunohistochemistry

Selected publications

Protein kinase D1, reduced in Human Pancreatic Tumors, Increases Secretion of Small Extracellular Vesicles From cancer Cells That Promote Metastasis to Lung in Mice. 

Armacki M, Polaschek S, Waldenmaier M, Morawe M, Ruhland C, Schmidt R, Lechel A, Tharehalli U, Steup C, Bektas Y, Li H, Kraus JM, Kestler HA, Kruger S, Ormanns S, Walther P, Eiseler T and Seufferlein T. Gastroenterology 2020; DOI: https://doi.org/10.1053/j.gastro.2020.05.052

Thiry-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failure.

Armacki M, Trugenberger AK, Ellwanger AK, Eiseler T, Schwerdt C, Bettac L, Langgartner D, Azoitei N, Halbgebauer R, Groß R, Barth T, Lechel A, Walter BM, Kraus JM, Wiegreffe C, Grimm J, Scheffold A, Schneider MR, Peuker K, Zeißig S, Britsch S, Rose-John S, Vettorazzi S, Wolf E, Tannapfel A, Steinestel K, Reber SO, Walther P, Kestler HA, Radermacher P, Barth TF, Huber-Lang M, Kleger A, Seufferlein T. J Clin Invest. 2018 doi: 10.1172/JCI97912.

Protein kinase D2 induces invasion of pancreatic cancer cells by regulating matrix metalloproteinases.

Wille C, Köhler C, Armacki M, Jamali A, Gössele U, Pfizenmaier K, Seufferlein T, Eiseler T. Mol Biol Cell. 2014. doi: 10.1091/mbc.E13-06-0334

A novel splice variant of calcium and integrin-binding protein 1 mediates protein kinase D2-stimulated tumour growth by regulating angiogenesis.

Armacki M, Joodi G, Nimmagadda SC, de Kimpe L, Pusapati GV, Vandoninck S, Van Lint J, Illing A, Seufferlein T. Oncogene. 2014. Feb 27;33(9):1167-80. doi: 10.1038/onc.2013.43.

Keratin 8 phosphorylation regulates keratin reorganization and migration of epithelial tumor cells.

Armacki M, Busch T,  Eiseler T, Joodi G, Temme C, Jansen J, von Wichert G, Omary MB, Spatz J, Seufferlein T. J Cell Sci. 2012. doi: 10.1242/jcs.080127.

Protein kinase D2 induces invasion of pancreatic cancer cells by regulating matrix metalloproteinases.

Wille C., Köhler C., Armacki M., Jamali A., Gössele U., Pfizenmaier K., Seufferlein T., Eiseler T. Mol Biol Cell. 2014 doi: 10.1091/mbc.E13-06-0334

Join our group

 

We continuously offer MD, Master and Bachelor positions. In case you are interested please send your application to:

milena.armacki@uniklinik-ulm.de