A woman’s breast cancer has spread to her bones or lungs, and a type of immune cell called a macrophage is actively helping the tumour grow there. For 30 years, the survival rate for metastatic breast cancer has not improved, largely because treatments have focused only on the tumour cells themselves. This research addresses a gap: the role of the surrounding tissue environment—specifically macrophages, which are abundant in tumours—in driving the cancer’s spread. The researcher has already shown that macrophages promote tumour growth by stimulating blood vessel formation, helping cancer cells invade and enter the bloodstream, and suppressing immune defences. If this work succeeds, it will identify the specific molecular signals macrophages use at each stage of metastasis—from the primary tumour to bone and lung sites. This could lead to drugs that target only the harmful macrophage populations, leaving beneficial immune cells intact. Combined with existing chemotherapy or radiotherapy, such treatments could finally improve outcomes for patients with metastatic breast cancer, a group that has seen no meaningful progress in three decades.
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In breast cancer the survival rate of women with metastatic disease has not changed for 30 years indicating the need to different treatment strategies. While research has largely focused upon tumor cells it has become apparent that progressive modification of the stromal microenvironment is equally as important in tumor progression to malignancy as the changes in the tumor cells themselves. In this environment macrophages are particularly abundant and I showed that they promote tumor progression to malignancy. These effects are through stimulation of angiogenesis, promotion of tumor cell invasion and intravasation, suppression of anti-tumor immune responses and at metastatic sites, promotion of extravasation and their subsequent tumor cell establishment and persistent growth. The aims of this application is to define the molecular bases of these activities through the metastatic cascade. This will enable development of macrophage sub-population specific reagents that can be combined with conventional therapies to improve the outcome of patients with metastasis disease. My four specific aims will elucidate the mechanisms of macrophage action on angiogenesis and tumor cell migration, invasion and intravasation in the primary tumor. At bone and lung metastatic site I will determine the mechanisms behind the macrophage stimulation of seeding and persistent growth. Strategically I will use innovative in vivo imaging combined with conditional genetic ablation in macrophages of ke y signaling molecules in mouse models. This will ascribe specific biological functions to individual macrophage populations. These studies will also be translated to human breast cancers and their modeling in humanized mice.
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