Targeting Neutrophil Extracellular Traps to Prevent Breast Cancer Metastasis Caused by Stress
Abstract
Rationale: Metastatic breast cancer is largely incurable and the cause of most breast cancer deaths. The majority of metastases originate from breast cancer cells that have spread, i.e., disseminated, to new organs before the primary tumor was diagnosed and treated. These cells can, even years after treatment of the original breast tumor, develop into metastasis. To prevent death from breast cancer metastasis, we must therefore understand the signals that drive disseminated breast cancer cells to form metastasis. One such signal is stress. As many as 20%-40% of breast cancer patients have high levels of anxiety or depression due to stress. Both chronic stress and poor coping ability are associated with reduced survival time in breast cancer but virtually nothing is known about why. We have now found that stress hormones called glucocorticoids drive metastasis by acting on a type of immune cell called neutrophils, causing them to form neutrophil extracellular traps (NETs). NETs are meshes of DNA and proteins that are formed as part of the immune response to bacteria. However, we previously showed that cancer can “hijack” this typically beneficial process to cause metastasis. Our data strongly support a model in which NETs shut down the immune system’s ability to kill disseminated cancer cells, allowing these cells to form metastases. We have found that NETs stimulate the production of interleukins, which are molecules that immune cells use to communicate with each other. The interleukins produced after stimulation by NETs inhibit the immune system’s ability to kill cancer cells. Objective: For the first time, we have determined that during stress, glucocorticoids induce neutrophils to form NETs and that the NETs, via interleukins, inhibit the immune killing of disseminated breast cancer cells. If we can determine exactly how glucocorticoids induce neutrophils to form NETs and how the NETs in turn shut down the immune response against the disseminated cancer cells, then we can develop strategies to prevent stress from causing lethal metastasis from disseminated breast cancer cells. Our project therefore addresses the overarching challenges of (1) identify why some breast cancers become metastatic; and (2) determine why/how breast cancer cells lie dormant for years and then re-emerge; determine how to prevent lethal recurrence. Aims: We first need animal models that recapitulate the key biological aspects of stress to facilitate our studies on how stress via NETs causes metastasis. In Aim 1, we will establish a comprehensive set of mouse models by combining models of different breast cancer subtypes with models of different types of stress and coping abilities (extensively used in research to develop drugs for mood disorders, including ketamine—a new drug to treat depression that was approved spring 2019). With these models, we will determine the effects of different types of stress and coping abilities on metastasis and the time required to recover from stress to avoid metastasis. As mentioned, we have discovered that glucocorticoids (including synthetic forms used to reduce nausea from chemotherapy) induce NETs. In Aim 2, we will determine how glucocorticoids induce NETs, as this information will facilitate the development of drugs that specifically target this process. We have already identified cyclin-dependent kinases (CDK) 4/6 (molecules that normally regulate cell growth) as targets to prevent glucocorticoid-induced NET formation. Therefore, we will test whether CDK4/6 inhibitors, currently used to treat breast cancer, can prevent stress-induced metastasis via their ability to block NET formation. We found that NETs stimulate the production of interleukins, which can then turn off the immune system’s ability to kill the disseminated breast cancer cells. In Aim 3, we will test whether drugs blocking these interleukins (already U.S. Food and Drug Administration [FDA]-approved to treat r
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010753
Entities
People
- Mikala Egeblad
Organizations
- Cold Spring Harbor Laboratory
- United States Army