Anti-myeloma strategies by re-establishing bone regeneration and hematopoietic niches
Final Report Abstract
In summary, we identified a characteristic genomic signature in skeletal precursor cells after physical interaction with myeloma cells. The transcriptome analyses reflect changes in the gene expression profiles that have previously been linked to malignancy and are supporting a tumor-induced bone loss. According to the analysis, intrinsic pro-osteogenic pathways are downregulated in MSC that may be mediated by enhanced expression of osteoclast-derived coupling factors, an imbalanced ratio of antianabolic/anabolic factors, and a potential commitment to the adipocyte lineage. Furthermore, this hampered osteogenesis is associated with enhanced pro-angiogenic activity. This uncoupling between angiogenesis and osteogenesis may be triggered by an enhanced expression of key factors, like ANGPTL4 and CYR61, which further promote MM cell adhesion, tumor relapse and development of secondary malignancies. The third identified factor, the KISS1R, provides a promising new opportunity for the diagnosis of MM bone disease. As a novel strategy it allows for targeting both the tumor cells and the host response to tumor arrival. This brings about an enhanced potential for monitoring especially early changes in bone microenvironment along disease development and also for treatment response. Our data reveal novel, potential trigger mechanisms and targets that trace the early processes of myeloma bone disease and offer new opportunities in the treatment scenario.
Publications
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Antiresorptiva in der Behandlung von Knochenmetastasen. In: Stenzl, Fehm, Hofbauer und Jakob (Herausgeber), Knochenmetastasen, Springer, Berlin, 2014, ISBN 973-3-662-43470-3
Jakob F, Ebert R
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Dickkopf-1 is regulated by the mevalonate pathway in breast cancer. Breast Cancer Res. 2014;16:R20
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
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Mesenchymal stem cell contact promotes CCN1 splicing and transcription in myeloma cells. Cell Commun Signal. 2014;12:36
Dotterweich J, Ebert R, Kraus S, Tower RJ, Jakob F, Schütze N
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Probenecid as a sensitizer of bisphosphonate-mediated effects in breast cancer cells. Mol Cancer. 2014;13:265
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
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Contact of myeloma cells induces a characteristic transcriptome signature in skeletal precursor cells – implications for myeloma bone disease. Bone. 2016;93:155-66
Dotterweich J, Schlegelmilch K, Keller A, Tower RJ, Klein-Hitpass L, Linden C, Geyer B, Ebert R, Jakob F, Schütze N
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The KISS1 Receptor as an in vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease. PLoS One. 2016;11:e0155087
Dotterweich J, Tower RJ, Brandl A, Müller M, Hofbauer LC, Beilhack A, Ebert R, Glüer C, Tiwari S, Schütze N, Jakob F
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Jam-A as a prognostic factor and new therapeutic target in multiple myeloma. Leukemia. 2018;32:736-43
Solimando AG, Brandl A, Mattenheimer K, Graf C, Ritz M, Ruckdeschel A, Stühmer T, Rudelius M, Dotterweich J, Ebert R, Frassanito MA, Rosenwald A, Vacca A, Einsele H, Jakob F, Beilhack A
