/project 5

R. Ebert, N. Schütze and F. Jakob, Würzburg

Targeting bone specific response to tumor growth for anti-myeloma strategy

Multiple myeloma (MM) inhibits bone and blood regeneration by various mechanisms, including stem cell niche conditioning with altered stem cell lineage commitment, uncoupling of angiogenesis and osteogenesis, and promotion of osteolytic vicious cycles. We have identified several new target mechanisms for modulating the stem cell niche and mesodermal commitment induced by contact between myeloma and MSC, such as
(I) impaired lineage commitment for osteogenesis and altered angiogenesis and adipogenesis (ROR1, BMPER);
(II) induction of new premetastatic niches and competitive hijacking of preformed stem cell niches (CXCR4/SDF-1, EBF2, JAM2/3); and
(III) progression of myeloma bone disease (KISS1R, proapoptotic signaling via GPR).
Based on these results we hypothesize that these targets can be addressed for sensitive molecular imaging, restoration of blood and bone regeneration and specific myeloma treatment.

Our specific aims for the second funding period are to target contact-induced/repressed candidates and signaling systems in order to:

(I) investigate the biological relevance of inhibitors for lineage commitment and of disintegrators of angiogenesis,

(II) elucidate molecular mechanisms of niche modulation and T-cell response in myeloma bone disease depending on local oxygen tension, and

(III) define the relevance of the KISS1R system for bone regeneration and its potential for imaging and site-specific targeting.
 

The general strategy is to evaluate lead candidates as diagnostic and therapeutic targets using stepwise characterization in 2D cell culture, 3D co-cultures in the BioVaSc device in bone marrow, preclinical models (e.g. MOPC315.BM) and validate these findings in human material from MM patients. These studies should paradigmatically integrate the bone and bone marrow niche into anti-tumor strategies. Reestablishing niches and pathways for bone and blood regeneration may confer anti-myeloma efficacy.


 

Dr. rer. nat. Regina Ebert
is group leader for "Stem Cell Biology" at the Orthopedic Center for Musculoskeletal Research at the University of Würzburg since 2002, where she also obtained her PhD in biology.


 

Prof. Dr. rer. nat. Norbert Schütze
Professor on unfixed term and technical Director of the Research Laboratories.
Research focus: Mesenchymal stem cells, cellular differentiation, functional investigation of CCN-family proteins, molecular elucidation of cell-cell interaction, global gene expression studies and extraction of biology

Prof. Dr. med. Franz Jakob
Head of Research, Orthopedic Center for Musculoskeletal Research, Chair Musculoskeletal Center Würzburg MCW, Orthopedic Department, University of Würzburg.
Training in Endocrinology and Cell Biology / Protein chemistry. Basic Research in Bone (Stem) Cell Biology, Bone Metastasis, Mesenchymal Tissue Regeneration. Clinical Osteology with a focus on Osteoporosis, Bone Metastasis, Metabolic Bone Diseases, Rare Diseases of bone (e.g. Paget´s Disease, Fibrous Dysplasia, Hypophosphatasia, Osteogenesis Imperfecta).


 
 
Project-related list of publications

 
Dotterweich J, Tower RJ, Brandl A, Müller M, Hofbauer LC, Beilhack A, Ebert R, Glüer CC, Tiwari S, Schütze N, Jakob F. The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease. PLoS One. 2016;11:e0155087.

Dotterweich J, Ebert R, Kraus S, Tower RJ, Jakob F, Schütze N. Mesenchymal stem cell contact promotes CCN1 splicing and transcription in myeloma cells. Cell Commun Signal. 2014;12:36. 
 
Ebert R, Meissner-Weigl J, Zeck S, Määttä J, Auriola S, Coimbra de Sousa S, Mentrup B, Graser S, Rachner TD, Hofbauer LC, Jakob F. Probenecid as a sensitizer of bisphosphonate-mediated effects in breast cancer cells. Mol Cancer. 2014;13:265.

Hofbauer LC, Rachner TD, Coleman RE, Jakob F. Endocrine aspects of bone metastases. Lancet Diabetes Endocrinol 2014;2:500-12.
 
Rachner TD, Göbel A, Thiele S, Rauner M, Benad-Mehner P, Hadji P, Bauer T, Muders MH, Baretton GB, Jakob F, Ebert R, Bornhäuser M, Schem C, Hofbauer LC. Dickkopf-1 is regulated by the mevalonate pathway in breast cancer. Breast Cancer Res 2014;16:20.
 
Schilling T, Ebert R, Raaijmakers N, Schütze N, Jakob F. Effects of phytoestrogens and other plant-derived compounds on mesenchymal stem cells, bone maintenance and regeneration. J Steroid Biochem Mol Biol 2014;139:252-61.

Schmitz P, Gerber U, Schütze N, Jüngel E, Blaheta R, Naggi A, Torri G, Bendas G. Cyr61 is a target for heparin in reducing MV3 melanoma cell adhesion and migration via the integrin VLA-4. Thromb Haemost 2013;110:1046-54.
 
Schmitz P, Gerber U, Jüngel E, Schütze N, Blaheta R, Bendas G. Cyr61/CCN1 affects the integrin-mediated migration of prostate cancer cells (PC-3) in vitro. Int J Clin Pharmacol Ther 2013;51:47-50.
 
Klotz B, Mentrup B, Regensburger M, Zeck S, Schneidereit J, Schupp N, Linden C, Merz C, Ebert R, Jakob F. 1,25-Dihydroxyvitamin D3 treatment delays cellular aging in human mesenchymal stem cells. PLoS One 2012;7:29959.

Benisch P, Schilling T, Klein-Hitpass L, Frey SP, Seefried L, Raaijmakers N, Krug M, Regensburger M, Zeck S, Schinke T, Amling M, Ebert R, Jakob F. The transcriptional profile of mesenchymal stem cell populations in primary osteoporosis is distinct and shows overexpression of osteogenic inhibitors. PLoS One 2012;7:45142.

Laug R, Fehrholz M, Schütze N, Kramer BW, Krump-Konvalinkova V, Speer CP, Kunzmann S. IFN-g and TNF-a synergize to inhibit CTGF expression in human lung endothelial cells. PLoS One 2012;7:e45430.

Ebert R, Zeck S, Meissner-Weigl J, Klotz B, Rachner TD, Benad P, Klein-Hitpass L, Rudert M, Hofbauer LC, Jakob F. Krüppel-like factors KLF2 and 6 and Ki-67 are direct targets of zoledronic acid in MCF-7 cells. Bone 2012;50:723-32.

Limbert C, Ebert R, Schilling T, Path G, Benisch P, Klein-Hitpass L, Seufert J, Jakob F. Functional signature of human islet-derived precursor cells compared to bone marrow-derived mesenchymal stem cells. Stem Cells Dev 2010;19:679-691.

Ebert R, Zeck S, Krug R, Meissner-Weigl J, Schneider D, Seefried L, Eulert J, Jakob F. Pulse treatment with zoledronic acid causes sustained commitment of bone marrow derived mesenchymal stem cells for osteogenic differentiation. Bone 2009;44:858-864.

Goebel S, Lienau J, Rammoser U, Seefried L, Wintgens KF, Seufert J, Duda G, Jakob F, Ebert R. FGF23 is a putative marker for bone healing and regeneration. J Orthop Res 2009;27:1141-1146.

Schilling T, Küffner R, Klein-Hitpass L, Zimmer R, Jakob F, Schütze N. Microarray analyses of transdifferentiated mesenchymal stem cells. J Cell Biochem 2008;103:413-433.

Schilling T, Noth U, Klein-Hitpass L, Jakob F, Schütze N. Plasticity in adipogenesis and osteogenesis of human mesenchymal stem cells. Mol Cell Endocrinol 2007;271:1-17.

Schütze N, Schenk R, Fiedler J, Mattes T, Jakob F, Brenner RE. CYR61/CCN1 and WISP3/CCN6 are chemoattractive ligands for human multipotent mesenchymal stroma cells. BMC Cell Biol 2007;8:45.

Ebert R, Ulmer M, Zeck S, Meissner-Weigl J, Schneider D, Stopper H, Schupp N, Kassem M, Jakob F. Selenium supplementation restores the antioxidative capacity and prevents cell damage in bone marrow stromal cells in vitro. Stem Cells 2006;24:1226-1235.

Schütze N, Nöth U, Schneidereit J, Hendrich C, Jakob F. Differential expression of CCN-family members in primary human bone marrow-derived mesenchymal stem cells during osteogenic, chondrogenic and adipogenic differentiation. Cell Commun Signal 2005;3:5.
 
Technische Universitt Dresden    Christian-Albrechts-Universitt zu Kiel    Julius-Maximilians-Universitt Wrzburg
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