Metastasis is the spread and outgrowth of cancer cells in organs distant from the site of origin. In breast cancer, the bone is the most common site of metastasis and metastatic outgrowth in the bone causes hundreds of thousands of deaths world-wide every year. In recent years it has become evident that stem cell characteristics play an important role in cancer progression and metastasis. These characteristics are not only intrinsically determined but also maintained and even induced by the microenvironment — the metastatic niche — suggesting a very complex interaction between cancer stem cells and their niches. We have identified an essential niche component for metastasis of breast cancer. This component is the extracellular matrix (ECM) protein tenascin C (TNC). We demonstrated, that in the context of lung metastasis, TNC engages stem cell signaling pathways to promote fitness of metastasis initiating cells. Moreover, we demonstrated that TNC is also crucial for breast cancer metastasis to bone. However, the cellular functions and signaling mediated by TNC and the surface receptors TNC engages in disseminated breast cancer cells growing into bone metastasis is unknown. We aim to address this in an integrative way using 3D culture systems of primary cancer cells, RNA interference, transcriptomic and proteomic screens, genetic- and xenograft -mouse models of cancer progression and metastasis. Moreover, we aim to use mouse models to address if inhibiting TNC, TNC-receptors or downstream signaling can sensitize bone metastasis to therapeutic intervention. Increasing evidence suggests that proteins of the extracellular matrix (ECM) support the fitness of disseminated cancer cells at distant sites, facilitating metastatic outgrowth. Targeting these components may provide the means to impair the competence of disseminated cancer cells and prevent metastatic relapse.
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