Target organ specific influences of macrophages on dormancy of disseminated tumorcells.
Final Report Abstract
Metastases originate from tumor cells that disseminate from the primary site and can occur years or decades after removal of the primary tumor, indicating that disseminated tumor cells (DTCs) can persist in a dormant state and eventually return to a proliferative state. Dissemination can already occur from from pre-invasive, i.e. pre-malignant (PM) lesions such as ductal carcinoma in situ (DCIS) and these early DTCs can form metastases, but only after long periods of dormancy. Whether DTCs become dormant or start proliferating and form metastases also seems to be dependent on the specific microenvironment in their target organ: dormant DTCs are commonly detected in the bone, whereas DTCs in the lung rather start proliferating and develop into metastatic lesions. However, little is known about the mechanisms of early dissemination and dormancy. Macrophages (MOs) have been shown to drive dissemination of tumor cells during late invasive stages and promote macrometastatic growth. We therefore hypothesized that MOs might also be involved in early dissemination and the escape from dormancy. Using the MMTV-ErbB2 mouse model, we found that MOs are localized inside the epithelium of pre-malignant lesions but localize in the stroma of healthy tissue. MO recruitment depends on upregulation of CCL2 in mammary epithelial cells via ErbB2-mediated activation of NFkB. MO invasion into ducts disrupts the myoepithelium and induces an epithelial-to-mesenchymal transition (EMT). Depletion of MOs from pre-malignant MMTV-ErbB2 mice drastically reduces early dissemination. Importantly, samples from patients with pre-invasive ductal carcinoma in situ frequently contain intra-epithelial MOs, correlating with reduced E-Cadherin expression. We were further able to show that bone MOs maintain DTCs in a dormant state whereas lung MO precursors have a growth-promoting effect. We have additionally identified that tissue MOs might influence DTC growth behavior by influencing TGFp2 levels in BM and lung. Overall, our data provide a new understanding of the natural history of disseminated cancer, which is largely incurable for reasons that might be linked to early dissemination and divergent evolution of metastasis. Based on the preliminary data created with this fellowship, the applicant was able to secure a highly competitive breast cancer postdoctoral fellowship of the Department of Defense to complete her studies and prepare for an independent group leader position.
Publications
- Integration of micro-environmental and stress signaling antagonizes colorectal cancer progression. Comment in EMBO Journal 2014 Aug 33(16):1737-9
Nina Linde, Sosa MS, Aguirre-Ghiso JA
(See online at https://dx.doi.org/10.15252/embj.201489364)
