| Breast cancer causes mortality by metastasizing to a variety of vital organs. Effective therapeutic intervention of metastasis relies on better mechanistic understanding. Both cancer cells and the host microenvironment are important in determining the efficiency of metastasis. The dissertation describes efforts to investigate tumor-microenvironment interactions in the context of organotropic metastatasis.The functions of metalloproteinases in organ-specific metastasis remain poorly defined. A mechanism is presented whereby ADAMTS1 and MMP1 orchestrate a paracrine pathway involving stromal EGF signaling to favor osteoclastogenesis and bone metastasis. MMP1 and ADAMTS1 in tumor cells, as well as EGFR in osteoblasts, are promising therapeutic targets for inhibiting bone metastasis.Breast cancer patients often develop metastasis many years after surgery, defining the clinical problem of tumor dormancy. Molecular understanding of dormancy and its breakdown is very limited. By characterizing a new bone metastasis model, VCAM1, upregulated in tumor cells, is shown to play an essential role in the transition from dormant micrometastasis to clinically manifest metastasis. By interacting with alpha4beta1, VCAM1 recruits osteoclast progenitors and elevates local osteoclast activity. Antibody against VCAM1 or alpha4beta1 efficiently blocks bone metastasis progression. This study establishes VCAM1 as a promising target for adjuvant and cytostatic therapy.Tumor hypoxia is known to activate angiogenesis, anaerobic glycolysis and metastasis. Our study, for the first time, defines distinct kinetics and functions of hypoxia in primary tumor and organotropic metastasis in the same cell system. Hypoxia enhances the expression of a significant number of genes in the lung metastasis signature, but only a few bone metastasis genes. Despite harnessing different mechanisms, metastases to both organs are markedly inhibited by blocking HIF-1alpha. A 45-gene hypoxia response signature efficiently stratifies breast cancer patients with low or high risks of lung metastasis. Our study demonstrates distinct functions of hypoxia in organotropic metastasis and establishes HIF-1alpha as a promising universal drug target.In the final study, we show that dual metastasis organotropisms can be acquired in the same cell through spontaneous cell fusion. The hybrids assimilate metastasis gene signatures from both parental cells and are genetically and phenotypically stable. This study suggests cell fusion as an efficient means of phenotypic evolution during tumor progression.Collectively, research presented in this dissertation identified multiple genes and pathways that play critical roles in the organ-specific metastasis process. They are promising therapeutic targets for controlling breast cancer metastasis. |
