/project 1

M. Bornhäuser and M. Wobus, Dresden

Modulation of the hematopoietic stem cell niche by micrometastases

Micrometastases of solid tumors like breast and prostate cancer have a predisposition to metastasize early to the bone marrow were they encounter the microenvironment of the hematopoietic stem cell niche. The molecular basis for the functional interaction between tumor cells with the cellular components of the bone marrow niche, e.g. hematopoietic stem cells (HSC) and mesenchymal stromal cells (MSC) remains only partially understood. Therefore, we investigate whether MSC and HSC are influenced in their genetic profile and function by the invading tumor cells and whether osteoclasts modulate the migration and homing of tumor cells into the bone marrow niche. We demonstrated a downregulation of SDF-1 expression levels in MSC by breast cancer cells which correlates with decreased HSC migration potential. Moreover, the tumor cells caused an enhanced TGFbeta1 expression and hampered the stromal network by downregulation of connexin-43 (Cx-43). In addition, we could show that the adhesion of HSCs to a MSC monolayer is significantly reduced by MCF-7 and MDA-MB231 breast cancer cells whereas MCF-10A non-malignant cells have no significant impact.
The overall goal of the project will be to delineate the impact of tumor cell invasion on the homeostasis of the bone marrow microenvironment and the identification of potential targets for therapeutic interventions.

Prof. Dr. med. Martin Bornhäuser is head of the stem cell transplant program and co-chair of the Med. Klinik and Poliklinik I together with Prof. Dr. med. Gerhard Ehninger. He is vice-speaker and board-member of the DFG excellence cluster “Center for Regenerative Therapies Dresden” (CRTD) and speaker of the research area hematology/oncology. His research topics include allogeneic stem cell transplantation, cellular therapy, adoptive immunotherapy, cell biology of mesenchymal and hematopoietic stem cells and targeted therapy.

Dr. rer. nat. Manja Wobus is senior scientist in the stem cell research lab of the department of hematology/oncology. With long-term experiences in molecular and cell biology her research interests are signalling pathways, genetic and proteomic profiles of tumor and stem cells and the interaction of different cell types of the bone marrow niche under physiological and pathophysiological conditions.

Project-related list of publications

Duryagina R, Anastassiadis K, Maitz M, Gramm S, Schneider S, Wobus M, Thieme S, Brenner S, Werner C, Bornhauser M. Cellular reporter systems for high-throughput-screening of interactions between bioactive matrices and human mesenchymal stromal cells. Tissue Eng Part C Methods 2014; in press
Duryagina R, Thieme S, Anastassiadis K, Werner C, Schneider S, Wobus M, Brenner S, Bornhäuser M. Overexpression of Jagged-1 and its intracellular domain in human mesenchymal stromal cells differentially affect the interaction with hematopoietic stem and progenitor cells. Stem Cells Dev 2013;22:2736-50.
Ferrer RA, Wobus M, List C, Wehner R, Schönefeldt C, Brocard B, Mohr B, Rauner M, Schmitz M, Stiehler M, Ehninger G, Hofbauer LC, Bornhäuser M, Platzbecker U. Mesenchymal stromal cells from patients with myelodyplastic syndrome display distinct functional alterations that are modulated by lenalidomide. Haematologica. 2013;98:1677-85.
Prewitz MC, Seib FP, von Bonin M, Friedrichs J, Stißel A, Niehage C, Müller K, Anastassiadis K, Waskow C, Hoflack B, Bornhäuser M, Werner C. Tightly anchored tissue-mimetic matrices as instructive stem cell microenvironments. Nat Methods 2013;10:788-94.
Rauner M, Stein N, Winzer M, Goettsch C, Zwerina J, Schett G, Distler JH, Albers J, Schulze J, Schinke T, Bornhäuser M, Platzbecker U, Hofbauer LC. WNT5A is induced by inflammatory mediators in bone marrow stromal cells and regulates cytokine and chemokine production. J Bone Miner Res 2012;27:575-85.
Stopp S, Bornhäuser M, Ugarte F, Wobus M, Kuhn M, Brenner S, Thieme S. Expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells regulates proliferation, differentiation, and maintenance of hematopoietic stem and progenitor cells. Haematologica 2013;98:505-13.

Fasslrinner F, Wobus M, Duryagina R, Müller K, Stopp S, Wehner R, Rauner M, Hofbauer LC, Schmitz M, Bornhäuser M. Differential effects of mixed lymphocyte reaction supernatant on human mesenchymal stromal cells. Exp Hematol 2012;40:934-44.

Wobus M, Benath G, Ferrer RA, Wehner R, Schmitz M, Hofbauer LC, Rauner M, Ehninger G, Bornhäuser M, Platzbecker U. Impact of lenalidomide on the functional properties of human mesenchymal stromal cells. Exp Hematol 2012;40:867-76.

Jing D, Wobus M, Poitz DM, Bornhäuser M, Ehninger G, Ordemann R. Oxygen tension plays a critical role in the hematopoietic microenvironment in vitro. Haematologica 2012;97:331-9.
Goedecke A, Wobus M, Krech M, Münch N, Richter K, Hölig K, Bornhauser M. Differential effect of platelet-rich plasma and fetal calf serum on bone marrow-derived human mesenchymal stromal cells expanded in vitro. J Tissue Eng Regen Med 2011;5:648-54.
Fonseca AV, Freund D, Bornhäuser M, Corbeil D. Polarization and migration of hematopoietic stem and progenitor cells rely on RhoA/ROCK I pathway and an active reorganization of the microtubule network. J Biol Chem 2010;285:31661-71.
Fierro FA, Brenner S, Oelschlaegel U, Jacobi A, Knoth H, Ehninger G, Illmer T, Bornhäuser M. Combining SDF-1/CXCR4 antagonism and chemotherapy in relapsed acute myeloid leukemia. Leukemia 2009;23:393-396.
Seib FP, Prewitz M, Werner C, Bornhäuser M. Matrix elasticity regulates the secretory profile of human bone marrow-derived multipotent mesenchymal stromal cells (MSCs). Biochem Biophys Res Commun 2009;389:663-667.
Seib FP, Franke M, Jing D, Werner C, Bornhäuser M. Endogenous bone morphogenetic proteins in human bone marrow-derived multipotent mesenchymal stromal cells. Eur J Cell Biol 2009;88:257-271.
Alberti K, Davey RE, Onishi K, George S, Salchert K, Seib FP, Bornhäuser M, Pompe T, Nagy A, Werner C, Zandstra PW. Functional immobilization of signaling proteins enables control of stem cell fate. Nat Methods 2008;5:645-650.
Oswald J, Steudel C, Salchert K, Joergensen B, Thiede C, Ehninger G, Werner C, Bornhäuser M. Gene-expression profiling of CD34+ hematopoietic cells expanded in a collagen I matrix. Stem Cells 2006;24:494-500.
Wobus M, Huber O, Hamann J, Aust G. CD97 overexpression in tumor cells at the invasion front in colorectal cancer (CC) is independently regulated of the canonical Wnt pathway. Mol Carcinog 2006;45:881-886.
Wobus M, Vogel B, Schmucking E, Hamann J, Aust G. N-glycosylation of CD97 within the EGF domains is crucial for epitope accessibility in normal and malignant cells as well as CD55 ligand binding. Int J Cancer 2004;112:815-822.

/project 4

A. Trauzold and H. Kalthoff, Kiel

Impact of inflammatory mechanisms on osteoblast-metastatic tumor cell interaction

The impact of pro-inflammatory cytokines in bone metastases of breast cancer cells has not yet been deeply studied in its complexity and interdependency. Recently, we discovered that the nuclear death receptors TRAIL-R1/-R2 regulate microRNA processing and epithelial-mesenchymal transition (EMT). In our project we will test the hypotheses I) that inflammatory cytokines contribute to EMT in osteotropic tumor cells, and II) that TRAIL-R1/2-mediated mechanisms of EMT induction stimulate bone metastases.


PD Dr. rer. nat. Anna Trauzold
Division of Molecular Oncology, Institute for Experimental Cancer Research, Comprehensive Cancer Center - North, Kiel
Research focus: inflammation and cancer, apoptosis-resistance mechanisms, non-apoptotic and apoptotic functions of death receptors (TRAIL-Rs, CD95, TNF-R1)

Prof. Dr. rer. nat. Holger Kalthoff
Division of Molecular Oncology, Institute for Experimental Cancer Research, Comprehensive Cancer Center - North, Kiel
Research focus: molecular resistance mechanisms of epithelial tumor cells, non-apoptotic (pro-inflammatory) mechanisms of death receptors, Immunosuppression in pancreatic cancer, clinically adapted murine tumor models and molecular imaging, detection and characterization of disseminated tumor cells

Project-related list of publications
Voigt S, Philipp S, Davarnia P, Winoto-Morbach S, Röder C, Arenz C, Trauzold A, Kabelitz D, Schütze S, Kalthoff H, Adam D. TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells. BMC Cancer 2014;14:74.
Haselmann V, Kurz A, Bertsch U, Hübner S, Olempska-Müller M, Fritsch J, Häsler R, Pickl A, Fritsche H, Annewanter F, Engler C, Fleig B, Bernt A, Röder C, Schmidt H, Gelhaus C, Hauser C, Egberts JH, Heneweer C, Rohde AM, Böger C, Knippschild U, Röcken C, Adam D, Walczak H, Schütze S, Janssen O, Wulczyn FG, Wajant H, Kalthoff H, Trauzold A. Nuclear death receptor TRAIL-R2 inhibits maturation of let-7 and promotes proliferation of pancreatic and other tumor cells. Gastroenterology 2014;146:278-90. 
Schem C, Bauerschlag D, Bender S, Lorenzen AC, Hamann S, Rösel F, Kalthoff H, Glüer CC, Jonat W, Tiwari S. Preclinical evaluation of an antiangiogenesis inhibitor as a single agent and in combination with zoledronic acid in a mouse model of bone metastases. BMC Cancer 2013;24;13:32. 
Hirner H, Günes C, Bischof J, Wolff S, Grothey A, Kühl M, Oswald F, Wegwitz F, Bösl MR, Trauzold A, Henne-Bruns D, Peifer C, Leithäuser F, Deppert W, Knippschild U. Impaired CK1 delta activity attenuates SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo. PLoS One 2012;7:29709.
Tiwari S, Schem C, Lorenzen AC, Kayser O, Wiese C, Graeff C, Peña J, Marshall RP, Heller M, Kalthoff H, Jonat W, Glüer CC. Application of ex vivo micro-computed tomography for assessment of in vivo fluorescence and plain radiographic imaging for monitoring bone metastases and osteolytic lesions. J Bone Miner Metab 2012;30:373-80. 

Zhou DH, Yang LN, Roder C, Kalthoff H, Trauzold A. TRAIL-induced expression of uPA and IL-8 strongly enhanced by overexpression of TRAF2 and Bcl-xL in pancreatic ductal adenocarcinoma cells. Hepatobiliary Pancreat Dis Int 2013;12:94-8.

Tiwari S, Egberts JH, Korniienko O, Köhler L, Trauzold A, Glüer CC, Kalthoff H. Assessment of anti-inflammatory tumor treatment efficacy by longitudinal monitoring employing sonographic micro morphology in a preclinical mouse model. BMC Med Imaging.2011;11:15.

Roos C, Wicovsky A, Müller N, Salzmann S, Rosenthal T, Kalthoff H, Trauzold A, Kürbitz C, Heise D, Redmer T, Goumas F, Arlt A, Lemke J, Rimbach G, Kalthoff H, Trauzold A. Epicatechin gallate and catechin gallate are superior to epigallocatechin gallate in growth suppression and anti-inflammatory activities in pancreatic tumor cells. Cancer Sci 2011;102:728-34.

Röder C, Trauzold A, Kalthoff H. Impact of death receptor signaling on the malignancy of pancreatic ductal adenocarcinoma. Eur J Cell Biol 2011;90:450-5.

Ehrenschwender M, Siegmund D, Wicovsky A, Kracht M, Dittrich-Breiholz O, Spindler V, Waschke J, Kalthoff H, Trauzold A, Wajant H. Mutant PIK3CA licenses TRAIL and CD95L to induce non-apoptotic caspase-8-mediated ROCK activation. Cell Death Differ 2010;17:1435-47.

Seher A, Henkler F, Kneitz C, Wajant H. Soluble and transmembrane TNF-like weak inducer of apoptosis differentially activate the classical and noncanonical NF-kappa B pathway. J Immunol 2010;185:1593-605.

Lemke J, Noack A, Adam D, Tchikov V, Bertsch U, Röder C, Schütze S, Wajant H, Kalthoff H,  Trauzold A.  TRAIL signaling is mediated by DR4 in pancreatic tumor cells despite the expression of functional DR5. J Mol Med 2010;88:729-740.

von Forstner C, Egberts JH, Ammerpohl O, Niedzielska D, Buchert R, Mikecz P, Schumacher U, Peldschus K, Adam G, Pilarsky C, Grutzmann R, Kalthoff H, Henze E, Brenner W. Gene expression patterns and tumor uptake of 18F-FDG, 18F-FLT, and 18F-FEC in PET/MRI of an orthotopic mouse xenotransplantation model of pancreatic cancer. J Nucl Med 2008;49:1362-1370.

Egberts JH, Cloosters V, Noack A, Schniewind B, Thon L, Klose S, Kettler B, von Forstner C, Kneitz C, Tepel J, Adam D, Wajant H,  Kalthoff H,  Trauzold A. Anti-tumor necrosis factor therapy inhibits pancreatic tumor growth and metastasis. Cancer Res 2008;68:1443-1450.

Egberts JH, Schniewind B, Pätzold M, Kettler B, Tepel J,  Kalthoff H,  Trauzold A. Dexamethasone reduces tumor recurrence and metastasis after pancreatic tumor resection in SCID mice. Cancer Biol Ther 2008;7:1044-1050.

Siegmund D, Klose S, Zhou D, Baumann B, Röder C, Kalthoff H, Wajant H, Trauzold A. Role of caspases in CD95L- and TRAIL-induced non-apoptotic signalling in pancreatic tumour cells. Cell Signal 2007;19:1172-1184.

Trauzold A, Siegmund D, Schniewind B, Sipos B, Egberts J, Zorenkov D, Emme D, Röder C, Kalthoff H*, Wajant H. TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma. Oncogene 2006;25:7434-7439. 

Trauzold A, Roder C, Sipos B, Karsten K, Arlt A, Jiang P, Martin-Subero JI, Siegmund D, Muerkoster S, Pagerols-Raluy L, Siebert R, Wajant H, Kalthoff H. CD95 and TRAF2 promote invasiveness of pancreatic cancer cells. FASEB J 2005;19:620-622.

Kremer M, Quintanilla-Martinez L, Fuchs M, Gamboa-Dominguez A, Haye S,  Kalthoff H, Rosivatz E, Hermannstädter C, Busch R, Höfler H, Luber B. Influence of tumor-associated E-cadherin mutations on tumorigenicity and metastasis. Carcinogenesis 2003;24:1879-1886.

Trauzold A, Wermann H, Arlt A, Schutze S, Schafer S, Oestern S, Roder C, Ungefroren H, Lampe E, Heinrich M, Walczak H, Kalthoff H. CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-κB contributes to apoptosis resistance in ductal pancreatic adenocarcinoma cells. Oncogene 2001;20:4258-4269.

/project 6

M. Kieslinger, Munich

Determining the supporting mesenchymal cell lineages and their interactions with multiple myeloma

Various tumor cells, including those from hematopoietic malignancies, home to the bone marrow and interact with osteoblasts and osteoclasts, disrupting normal bone biology and hematopoiesis. As the most immature hematopoietic cells are affected in most cases, and osteoblasts are part of their supportive microenvironment, it is likely that the tumor cells interfere with these niche cells. Our group has identified a subset of osteoblastic cells (IEO) as a niche for hematopoietic stem cells, and is able to identify and isolate those in vivo.
The aim of this project is to investigate if IEO cells define a niche also for tumour cells in the bone marrow and are functionally required for this supportive role. To date, we have identified a novel secreted protein of 17kDA that is secreted by IEO cells and that is necessary for the support of normal hematopoietic stem cells. This protein is already implicated in the proliferation of cells from several different tumor types, and we are now investigating if this function is provided by IEO cells.

Dr. rer. nat. Matthias Kieslinger began his work on the differentiation of normal and malignant hematopoietic cells and has later extended his focus on bone biology. He started his own research group at the institute of clinical molecular biology and tumor genetics at the Helmholtz Center in Munich and is examining the interplay between these two fields.

Project-related list of publications

Jin S, Kim J, Willert T, Klein-Rodewald T, Garcia-Dominguez M, Mosqueira M, Fink R, Esposito I, Hofbauer LC, Charnay P, Kieslinger M. Ebf factors and MyoD synergistically regulate muscle relaxation via Atp2a1. Nature Comm 2014; in press.

Kim J, Badaloni A, Willert T, Zimber-Strobl U, Kühn R, Wurst W, Kieslinger M. A miRNA-based approach to down-regulate a gene family in vivo. PLOS One 2013;8:80312.

Kieslinger M, Hiechinger S, Dobreva G, Consalez GG, Grosschedl R. Early B cell factor 2 regulates homeostasis of hematopoietic stem cells in a cell non-autonomous manner. Cell Stem Cell 2010;7:496-507.
Dolznig H, Grebien F, Deiner EM, Stangl K, Kolbus A, Habermann B, Kerenyi MA, Kieslinger M, Moriggl R, Beug H, Müllner EW. Erythroid progenitor renewal versus differentiation: genetic evidence for cell autonomous, essential functions of EpoR, Stat5 and the GR. Oncogene 2006;25:2890-2900.
Kieslinger M, Folberth S, Dobreva G, Dorn T, Croci L, Erben R, Consalez GG, Grosschedl R. EBF2 Regulates osteoblast-dependent differentiation of osteoclasts. Dev Cell 2005;9:757-767.
Medina KL, Pongubala JM, Reddy KL, Lancki DW, Dekoter R, Kieslinger M, Grosschedl R, Singh H. Assembling a gene regulatory network for specification of the B cell fate. Dev Cell 2004;7:607-617.
Kieslinger M, Woldman I, Moriggl R, Hofmann J, Marine JC, Ihle JN, Beug H, Decker T. Antiapoptotic activity of Stat5 required during terminal stages of myeloid differentiation. Genes Dev 2000;14:232-244.
Dahl R*, Kieslinger M*, Beug H, Hayman MJ. Transformation of hematopoietic cells by the Ski oncoprotein involves repression of retinoic acid receptor signaling. Proc Natl Acad Sci USA 1998;95:11187-11192. (*equal contribution)

Technische Universitt Dresden    Christian-Albrechts-Universitt zu Kiel    Julius-Maximilians-Universitt Wrzburg
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