Human brain metastatic stroma attracts breast cancer cells via chemokines CXCL16 and CXCL12

The tumor microenvironment is composed of heterogeneous populations of cells, including cancer, immune, and stromal cells. Progression of tumor growth and initiation of metastasis is critically dependent on the reciprocal interactions between cancer cells and stroma. Through RNA-Seq and protein analyses, we found that cancer-associated fibroblasts derived from human breast cancer brain metastasis express significantly higher levels of chemokines CXCL12 and CXCL16 than fibroblasts from primary breast tumors or normal breast. To further understand the interplay between cancer cells and cancer-associated fibroblasts from each site, we developed three-dimensional organoids composed of patient-derived primary or brain metastasis cancer cells with matching cancer-associated fibroblasts. Three-dimensional CAF aggregates generated from brain metastasis promote migration of cancer cells more effectively than cancer-associated fibroblast aggregates derived from primary tumor or normal breast stromal cells. Treatment with a CXCR4 antagonist and/or CXCL16 neutralizing antibody, alone or in combination, significantly inhibited migration of cancer cells to brain metastatic cancer-associated fibroblast aggregates. These results demonstrate that human brain metastasis cancer-associated fibroblasts potently attract breast cancer cells via chemokines CXCL12 and CXCL16, and blocking CXCR6-CXCL16/CXCR4-CXCL12 receptor–ligand interactions may be an effective therapy for preventing breast cancer brain metastasis. Metastasis: brain metastases fuel further spread Breast cancer metastases to the brain secrete signaling molecules that promote additional cancer cells to migrate there. Peter P. Lee and colleagues from the City of Hope in Duarte, California, USA, analyzed protein and gene expression levels in brain metastases, and showed that it is the stromal cells (support cells such as fibroblasts), rather than the cancer cells themselves, that are the source of these homing signals. When compared against stromal cells derived from primary breast tumors or healthy breast tissue, they found that the stromal cells that had lodged themselves in the brain expressed the highest levels of CXCL12 and CXCL16, two chemokines involved in cell movement. Using three-dimensional aggregates, the researchers showed that these metastatic stromal cells promoted cancer cells migration more potently than stromal cells from primary tumors or normal breast tissues. Blocking the chemokine activity or th