Abstract
Cathepsin S expression in tumor cells and stromal macrophages regulates breast-to-brain metastasis.
Major finding: Cathepsin S expression in tumor cells and stromal macrophages regulates breast-to-brain metastasis.
Mechanism: Cathepsin S promotes tumor cell transmigration across the blood–brain barrier via cleavage of JAM-B.
Impact: Inhibition of cathepsin S specifically impairs metastatic seeding and colonization in the brain.
Tumor cell dissemination is regulated by factors within the primary tumor microenvironment, including proteases such as cathepsins. However, the contribution of tumor–stromal interactions at distant sites to tumor progression and organ-specific metastatic tropism remains unclear. Using a xenograft model of tissue-specific breast cancer metastasis and a dual-species microarray platform, Sevenich and colleagues determined the differential expression of proteolytic effector genes in human tumor cells and murine stromal cells from tissues to which breast cancer frequently metastasizes, including brain, bone, and lung, at distinct stages of metastasis. Variation in tumor cell–specific gene expression was predominantly associated with differences between early-stage metastatic seeding and late-stage metastatic outgrowth, whereas stromal genes were differentially expressed in both a tissue-specific and stage-specific manner. In particular, cathepsin S expression exhibited a reciprocal expression pattern in tumor and stromal cells, with elevated tumor cell expression during early brain-specific metastasis and increased expression in stromal macrophages in late-stage brain metastases. High cathepsin S expression at the primary site was specifically associated with reduced brain metastasis–free survival in patients with breast cancer, suggesting that this protease may modulate organ-specific metastasis. Consistent with this idea, concomitant depletion of tumor and stromal cathepsin S, but not silencing of either source alone, decreased experimental brain metastasis in mice. Expression of cathepsin S in both cell types was required for metastatic seeding and outgrowth in the brain and promoted the transmigration of metastatic cells across the blood–brain barrier (BBB) via cleavage of the extracellular domain of junctional adhesion molecule B (JAM-B), which is required to maintain the integrity of tight junctions in the BBB and was expressed in the brain but not bone or lung. Furthermore, pharmacologic inhibition of cathepsin S specifically impaired brain metastasis in mice. These results identify cathepsin S as a critical modulator of organ-specific metastasis and a potential therapeutic target for metastatic breast cancer.
