Mikala Egeblad (virtual), NETworking in cancer: bidirectional interplay between neutrophils and tumors drives metastasis

Mikala Egeblad is Bloomberg Distinguished Professor of Tumor Microenvironment at the Johns Hopkins University School of Medicine.

Appointments/Affiliations

Research Topic

The Egeblad lab studies the contributions of the tumor microenvironment – in which cancer cells arise and live – to therapy responses and metastasis. Solid tumors are abnormally organized tissues that contain not only cancer cells, but also various stromal cell types and extracellular matrix, and these latter components constitute the microenvironment. Communications between the different components of the tumor influence its growth, its response to therapy, and its ability to metastasize. The lab studies the importance of tumor-stroma communications using co-culture assays and mouse models of breast and pancreatic cancer. We use co-culture assays to interrogate signaling pathways involved in communications between cancer cells and specific types of stromal cells (e.g., macrophages, neutrophils and fibroblasts). We use microscopy of tumors in live mice to determine how interactions between cancer and stromal cells or activation of specific signaling pathways influence cellular survival, proliferation and migration. We use bioluminescence and small animal ultrasound to follow tumor progression and regression at the organism level. Our main focus is on the functions of myeloid-derived immune cells, a diverse group of cells that can enhance angiogenesis and metastasis and suppress the response to chemotherapy and the cytotoxic immune responses against tumors. We study how different types of myeloid cells are recruited to tumors and how signals between them and the cancer cells, or other immune cells, influence response to chemotherapy and metastatic spread.

Abstract:

Chronic stress is associated with increased risk of metastasis and poor survival in cancer patients. Yet, the reasons for these associations are unclear. We show that chronic stress increased lung metastasis from disseminated cancer cells 2-4-fold in mice. Chronic stress significantly altered the lung microenvironment, with fibronectin accumulation, reduced T cell infiltration, and increased neutrophil infiltration. Depleting neutrophils abolished the stress-induced metastasis, indicating neutrophils’ critical role. Chronic stress shifted the normal circadian rhythm of neutrophils and, via glucocorticoids release, caused increased neutrophil extracellular trap (NET) formation. Importantly, in mice with neutrophil-specific glucocorticoid receptor deletion, chronic stress failed to increase NET levels and metastasis. Furthermore, digesting NETs with deoxyribonuclease (DNase) I prevented chronic stress-induced metastasis. Together, our data show that glucocorticoids released during chronic stress cause the formation of NETs and establishment of a metastasis-promoting microenvironment. Therefore, NETs could be targets for preventing metastatic recurrence in cancer patients, many of whom will experience chronic stress due to their disease.