Necrosis-mediated circulating tumor cell dissemination

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ABSTRACT Circulating tumor cells (CTCs) give rise to metastases, the major cause of cancer patient mortality. Despite its long-standing importance, what mediates CTC dissemination remains incompletely understood. One barrier has been the rarity of CTCs in patients and even more so in mouse models. Recently, I have developed an in vivo metastasis model for CTCs using rats. Compared with mice, I can robustly collect 10 to 20 times more blood using rats and obtain many more CTCs. Importantly, I observed that high CTC burden is associated with intratumoral necrosis, a form of inflammatory cell death. Furthermore, I have found temporal correlation between increase in intratumoral necrosis and CTC dissemination where there is a sudden 380-fold increase in CTC counts coinciding with increase in necrosis in the primary tumor. I hypothesize that necrosis in the primary tumor induces a high CTC dissemination state. I will test this hypothesis by 1) determining whether necrosis in the primary tumor is sufficient and necessary for a high CTC dissemination state 2) investigating whether CTC dissemination preferentially occurs in the necrotic regions of the primary tumor and 3) identifying necrotic tumor microenvironment markers associated with high CTC dissemination states. Uncovering the relationship between necrosis and CTC dissemination could enable selecting patients with necrotic tumors or surrogate serum markers of necrosis for more aggressive therapy to disrupt the metastatic process, thereby decreasing cancer patient mortality.