Influence of the skeletal remodeling status on tumor cell dissemination and metastatic outgrowth

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The bone matrix is continuously remodeled through the balanced activities of two substantially different cell types, bone-forming osteoblasts and bone-resorbing osteoclasts. Our Institute has a long expertise in bone-specific cellular and molecular characterization of genetically modified mouse models, and we have identified several key mechanisms controlling skeletal remodeling in the last years. For the present proposal we will continue our ongoing collaboration with the group of Prof. Klaus Pantel to address the question, if and how an impaired bone remodeling status affects tumor cell dissemination and metastatic outgrowth in vivo.For that purpose we will inject human and murine breast cancer cells into mice to study skeletal metastasis formation as well as changes in the bone microenvironment by Luciferase reporter gene assays, µCT, undecalcified histology and bone-specific histomorphometry. Most importantly, and in contrast to the majority of previously published studies, we do not aim at modifying the seed (i.e. the tumor cells), but the soil (i.e. the recipient mouse). To achieve our goals we have backcrossed different mouse models into genetic backgrounds (BALB/c and NSG) allowing xenotransplantation or syngeneic transplantation of cancer cells. While three of the models (Calca-/-, Calcr-/- and Notch2+/HCS) display specific disturbances of the coupling mechanisms required to synchronize bone formation and bone resoprtion, the other four models (Lrp5+/HBM, Col1a1-Sost, Col1a1-Krm2 and Col1a1-tTA;pTet-Wnt1) display selective changes in osteoblast activity. Since all these genetically modified mouse models have been previously analyzed to define not only their bone remodeling status, but also the molecular causes of the observed phenotypes, we expect that our results will clearly identify, which bone remodeling cell type is primarily involved in the suggested detrimental crosstalk between bone and tumor cells.In addition to this in vivo approach we will perform ex vivo co-culture experiments with breast cancer and bone remodeling cells to define specific molecular interactions. Although our project principally follows an unbiased approach, there are some hypotheses that will be addressed. For instance, since we have previously found that calcitonin (CT) controls bone formation by inhibiting the release of sphingosine 1-phosphate (S1P) from osteoclasts, we will analyze if CT, S1P and/or antagonists of specific S1P receptors will influence proliferation and/or migration of cancer cells, cultured alone or together with bone remodeling cell types.