Unraveling tumor-microenvironmental communication in nascent bone metastasis utilizing zebrafish xenografts

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Bone metastasis contributes strongly to metastatic cancer-related death and co-morbidity. Despite its importance, mechanisms underlying bone metastasis remain poorly understood. Communication of the tumor microenvironment (TME) with the cancer cells leads to enhanced cell survival, treatment resistance, and metastasis. The in vivo study of bone metastasis is limited due to the poor accessibility of bone tissue. Therefore, we propose to utilize the zebrafish to model metastatic colonization of hematopoietic tissue by human breast and prostate cancer cells. The transparent zebrafish larva allows efficient visualization of the entire process of early metastasis by live high-resolution imaging, on a whole animal level, as well as genetic modulation of the process. To study the TME communication, we have developed a zebrafish model in which TME cells change color upon interaction with engrafted human cancer cells allowing to define interactions of circulating and disseminated tumor cells with the hematopoietic niche, the equivalent of the bone niche. Overall aim is to utilize this system to determine the shared genetic signature of the TME post-engraftment of different osteotropic cells. Additionally, we will compare the individual osteotropic cells with their maternal line to identify genes whose expression is correlated with enhanced hematopoietic niche engraftment. A bioinformatic analysis will be used to identify the most promising candidate genes as well as signaling pathways potentially controlling the TME-cancer-axis. Candidate genes and pathways will be validated by a semi-high throughput F0 crispant or pharmacological inhibitor screen. The most promising targets will be validated in vitro and in vivo mammalian systems. Finally, candidate gene expression will be assessed in human breast cancer and bone metastasis tissue. Collectively, our analysis will identify novel mechanisms of breast and prostate cancer cell colonization into the bone as well as potential markers for early diagnosis and specific targeting of bone metastases towards precision medicine.