Dr Bin-Zhi Qian

Edinburgh Cancer Research UK Centre and

MRC University of Edinburgh Centre for Reproductive Health

Abstract:

Metastasis and therapy resistance are the major cause of breast cancer related lethality. Macrophages, a type of innate immune cells, are abundantly found in the tumor microenvironment and enhance malignancy. Using intra-vital imaging, we have shown that macrophages can directly promote tumour cell escape from primary tumour. We have also characterized a distinct population of macrophages that promote cancer recurrence following chemotherapy and identified the molecular mechanisms that mediate their tumour promoting function. In distal metastasis, we have identified a distinct population of metastasis-associated macrophages (MAMs) that promotes tumor cell extravasation, seeding and persistent growth in lung. These macrophages are derived from circulating inflammatory monocytes recruited by CCL2/CCR2 chemokine signaling and directly promote tumour cell extravasation and metastatic seeding in vivo. Using cell type specific genetic ablation we show that the molecular mechanism is in part through VEGF secretion by MAMs that increases vascular permeability. Our recent data suggest that this inflammatory monocyte-dependent mechanism is preserved in breast cancer metastasis to bone but not to liver using in vivo models. Gene expression profiling using FACS sorted metastasis associated macrophages identified specific gene expression signatures. Furthermore, distinct macrophage subsets were identified that promote metastatic outgrowth. Together, our data illustrated the heterogeneity of macrophages in cancer metastasis and therapy resistance, and suggested the therapeutic potential of targeting specific macrophage subsets in treating metastatic breast cancer.