Abstract 75: Impaired metastatic seeding underlies concomitant tumor resistance

Cancer metastasis, the spread of cancer cells from the primary tumor to distant organs, is responsible for poor overall survival of cancer patients even with advances in the development of targeted therapeutics. One of the reasons behind failure of current treatments is the continuous evolution of tumor cells and of their microenvironment at both the primary and distant sites, which leads to drug resistance. Primary tumor-derived signals such as secreted chemokines, cytokines, and growth factors can alter the host microenvironment at the metastatic site, leading to the recruitment of immune cells and to the formation of pre-metastatic microenvironments which promote metastasis. However, in some cases, primary tumor-derived signals have also been shown to have metastasis-suppressive effects, a phenomenon known as concomitant resistance. For example, unexpected increase in metastatic outgrowth upon surgical resection of a primary tumor has been reported for some breast cancer patients. Loss of concomitant resistance is a barrier to surgical intervention of primary tumor. This is currently being managed by chemotherapy and further identification of actionable mechanisms behind this phenomenon is necessary. The molecular mechanisms leading to concomitant resistance are poorly understood, and it remains poorly defined how this phenomenon evolves over time, during tumor progression. To investigate the effect of tumor progression on metastasis efficiency, non-tumor bearing (naïve) and tumor bearing mice were challenged with tail-vein injection of tumor cells and lung metastases were quantified. Our data indicate that primary tumors inhibit overt lung metastasis by impairing the ability of circulating tumor cells to seed in the lungs. Through time course studies, we found that early-stage (day 7 and 14) tumors impede early metastatic seeding, but later-stage tumors (day 28 and 35) do not. While adaptive immunity, involving T cells, can inhibit metastasis, results from depletion experiments suggest that the observed effect is T and B cell independent. Platelets can bind circulating tumor cells and recruit neutrophils at metastatic sites to facilitate seeding. We discovered that platelet activation and neutrophil recruitment to platelet-tumor cell clusters are impaired in tumor-bearing mice, suggesting that defects in these immune cell-tumor cell interactions might cause concomitant tumor resistance. Overall, our study uncovered that inefficient metastatic seeding m