The role of neutrophils in the formation of brain metastases

The development of metastases remains the leading cause of death in cancer patients. Of all metastasizing cancers, those that are able to colonize organs of the central nervous system, such as the brain, represent a particularly difficult challenge due to the uniqueness of the brain tissue architecture. Brain metastases frequently arise from melanoma, lung and breast cancers. While considerable advances have been made recently in treating these cancers at the primary site, a steep increase in mortality is observed in patients with brain metastases. This is partly due to our limited knowledge about the dynamic interplay between the brain microenvironment and brain metastasis formation, which directly translates into a dearth of clinical treatment options. By analysing brain metastasis patient samples, the Joyce lab has recently identified neutrophils, the largest circulating white blood cell population in humans, among the most abundant immune cells in these tumors. Moreover, they previously found that neutrophils are major contributors to breast-to-lung metastasis in obese individuals. These findings add to a handful of studies demonstrating cancer-regulating roles for neutrophils in different contexts. In this project, we therefore aim to now unravel how neutrophils may contribute to the seeding and metastatic outgrowth of cancer cells in the brain. The functional role of neutrophils during different steps of brain metastatic colonization will be investigated by addressing three complementary objectives. In the first aim, gene expression profiles of neutrophils isolated from human brain metastasis tissue will be compared to neutrophils from matched patient blood samples or from healthy donor blood. In the second aim, neutrophils will be depleted in state-of-the art mouse models of brain metastasis to explore their contributions during different stages of the metastatic cascade. Finally, identified candidate genes will be investigated using cell-based assays to understand potential alterations in neutrophil behaviour (such as migration capacity or production of reactive chemicals). These experiments aim to explore the mechanisms by which cancer cells can educate neutrophils in order to facilitate their malignant progression in the brain. This proposal comprises the first in-depth study of neutrophil roles during different stages of cancer progression to the brain. Combining the analysis of human brain metastasis tissue with state-of-the-art mouse models represents an unprecedented, comprehensive strategy to explore how neutrophils may contribute to brain metastasis formation. Together, these studies will significantly enhance our understanding of neutrophil functions during metastatic progression and may have important implications for the development of new treatment modalities for brain metastases in the future.