Development of a novel "all-human" animal model to study breast cancer metastasis to bone - comparison of transcriptional signatures from ex vivo cultured primary tumor cells and in vivo metastatic populations.
General and Visceral Surgery
Final Report Abstract
New therapeutic strategies against bone metastasis are still missing. Studies have even shown that more than 80 % of novel drug candidates fail when tested in the clinic. This is primarily due to the lack of appropriate preclinical models that make it possible to recapitulate the key steps of the human disease as most animal models don’t account for the obvious cellular and molecular differences between rodents and humans. Therefore the DFG fellow has entered new avenues by developing tissue engineered constructs composed of biomimetic scaffolds and human mesenchymal progenitor cells and their matrix products to mimic functionally and morphologically defined humanized organoids within immuno-compromized murine hosts. Human breast and prostate cancer cells injected into the vascular system of the mice homed to the humanized constructs and developed bone metastases. Human haematopoietic stem cells were also shown to home to the humanized ossicles and develop a humanized immune system. The model presented could potentially satisfy the need for a preclinical platform in which both human cancer cells and human immune cells can be manipulated within a humanized microenvironment.
Publications
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How smart do biomaterials need to be? A translational science and clinical point of view. Adv Drug Deliv Rev. 2013;65:581-603
Holzapfel BM, Reichert JC, Schantz JT, Gbureck U, Rackwitz L, Noth U, Jakob F, Rudert M, Groll J, Hutmacher DW
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Humanised xenograft models of bone metastasis revisited: novel insights into species-specific mechanisms of cancer cell osteotropism. Cancer Metastasis Rev. 2013;32:129-45
Holzapfel BM, Thibaudeau L, Hesami P, Taubenberger A, Holzapfel NP, Mayer-Wagner S, Power C, Clements J, Russell P, Hutmacher DW
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A tissue-engineered humanized xenograft model of human breast cancer metastasis to bone. Dis Model Mech. 2014;7:299-309
Thibaudeau L, Taubenberger AV, Holzapfel BM, Quent VM, Fuehrmann T, Hesami P, Brown TD, Dalton PD, Power CA, Hollier BG, Hutmacher DW
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Species-specific homing mechanisms of human prostate cancer metastasis in tissue engineered bone. Biomaterials. 2014;35:4108-15
Holzapfel BM, Wagner F, Loessner D, Holzapfel NP, Thibaudeau L, Crawford R, Ling MT, Clements JA, Russell PJ, Hutmacher DW
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Tie-2 regulates the stemness and metastatic properties of prostate cancer cells. Oncotarget. 2015 [Epub ahead of print]
Tang KD, Holzapfel BM, Liu J, Lee TK, Ma S, Jovanovic L, An J, Russell PJ, Clements JA, Hutmacher DW, Ling MT
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Tissue engineered humanized bone supports human hematopoiesis in vivo. Biomaterials. 2015; 61: 103-14
Holzapfel BM, Hutmacher DW, Nowlan B, Barbier V, Thibaudeau L, Theodoropoulos C, Hooper JD, Loessner D, Clements JA, Russell PJ, Pettit AR, Winkler IG, Levesque JP
