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