Organ specific macrophages and the regulation of disseminated tumor cell fate

DESCRIPTION (provided by applicant): The vast majority of breast cancer deaths are due to metastases. These can occur years or decades after removal of the primary tumor, which is mainly due to dormancy of solitary disseminated tumor cells (DTCs). This suggests that there is a rather broad window of opportunity to prevent metastatic outgrowth. However the development of metastasis-preventing therapies is limited by our poor understanding of DTC biology. We previously showed that the bone marrow microenvironment instructs DTCs to enter a persistent dormancy that is induced by high levels of TGF?2 in this microenvironment. In contrast, in the lung microenvironment that contains lower levels of TGF?2, DTC dormancy is short-lived and metastatic growth commonly ensues. Macrophages (M? are known to be crucial for macro-metastasis growth in the lung but their interaction with solitary DTCs and organ-specific functions have hardly been addressed. Our preliminary data indicate that bone M?might be the source of TGF?2 or instruct other stromal cells to make TGF?2 and prevent the growth of mammary carcinoma cells. In contrast, lung M?seem to be required to support DTC growth by at least limiting TGF?2 in this organ. We hypothesize that bone resident M?produce TGF?2 and possibly other dormancy instructing factors whereas lung M? produce factors that promote DTC proliferation or that antagonize TGF?2 production. Our goals are to 1. analyze the effect of lung and bone M?on DTC growth, and 2. identify M?erived factors that mediate the dormancy / growth decision of DTCs by comparing the expression profiles of lung and bone M? Our rationale is that a better understanding of how M?regulate target organ specific dormancy will first identify a stromal cell type instructive of dormancy vs. proliferation and this might lead to the development of therapies that eradicate dormant DTCs and prevent the occurrence of incurable metastases. The R03 mechanism will allow us to test the feasibility of our hypothesis within this small, self-contained research project.