/project 5
R. Ebert, N. Schütze and F. Jakob, WürzburgTargeting 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.
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Dr. rer. nat. Regina Ebert |
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Prof. Dr. rer. nat. Norbert Schütze |
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Prof. Dr. med. Franz Jakob |
Project-related list of publications
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.
Hofbauer LC, Rachner TD, Coleman RE, Jakob F. Endocrine aspects of bone metastases. Lancet Diabetes Endocrinol 2014;2:500-12.
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.
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.
