Modulation of the hematopoietic stem cell niche by micrometastases

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Micrometastases of solid tumors like breast and prostate cancer have a predisposition to metastasize early to the bone marrow were they encounter the microenvironment of the hematopoietic stem cell niche. The molecular basis for the functional interaction between tumor cells with the components of the bone marrow niche remains only partially understood. Therefore, we will test the hypothesis I) whether the cellular components of the hematopoietic stem cell niche (mesenchymal stromal cells, MSC, and hematopoietic stem cells, HSC) are influenced in their genetic profile and function by the invading tumor cells; and II) whether osteoclasts modulate the migration and homing of tumor cells into the bone marrow niche. Preliminary own data suggest that mRNA and protein levels of the chemokine stroma-derived factor-1α (SDF-1) are decreased after MSC incubation with tumor cell-conditioned medium in a time-dependent and reversible manner. The specific induction/repression of osteogenic signaling pathways as well as the secretion of proinflammatory cytokines after tumor cell contact and the potential role of osteoclasts in this context will be investigated. The overall goal of the project will be to delineate the impact of tumor cell invasion on the homeostasis of the bone marrow microenvironment and the identification of potential targets for therapeutic interventions.