Defining brain-body feedback loops mediating stress-induced metastasis - Evidence from human epidemiological studies and animal models reveals that chronic psychological stress influences the evolution, dissemination, and treatment results of neoplasia. Chronic stress is transduced into a physiological signal primarily via the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). Within the brain, corticotrophin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (PVNCRH neurons) integrate incoming sensory information and trigger glucocorticoid (GC) release from the adrenal gland. These neurons also promote the release of the adrenergic neurotransmitter norepinephrine (NE) throughout the body via the SNS. This positions PVNCRH neurons as central players in both the sensation and systemic response to stress. Cancer patients undoubtedly experience chronic stress (e.g., prognosis-related), and this stress is strongly linked to an increased risk of metastasis/recurrence. Yet, how stress promotes metastasis is poorly understood. Closing this knowledge gap is challenging given the involvement of multiple organ systems and the need to bridge different scientific disciplines. We assembled an interdisciplinary team to elucidate the mechanisms connecting stress and metastasis. By introducing chronic stress protocols in mouse models of metastatic breast and pancreatic cancer, we uncovered that HPA-axis-driven GC release triggers neutrophil extracellular trap (NET) formation, which is crucial for stress-induced micro-metastasis establishment from disseminated cancer cells. Furthermore, we detected stress-induced SNS activation at the metastatic site. Notably, chronic stress also caused resistance to immune checkpoint blockade (ICB), likely via the actions of both GCs and NE. Finally, we found that the presence of metastasizing cancer itself hyperactivates PVNCRH neurons. Thus, our findings establish a maladaptive stress-metastasis feedforward loop involving the HPA axis, SNS, and immune system: stress ► PVNCRH neuron activation ► SNS & HPA-axis activation ► metastasis progression ► PVNCRH neuron hyperactivation. Here, we propose to investigate how stress impacts metastasis and ICB responses, and how metastasis, in turn, drives the activity of this feedforward loop. In Aim 1, we will address how GCs cause NET formation and how NETs promote metastasis. In Aim 2, we will determine how the SNS influences the response to ICB therapy, employing a novel technique to manipulate the sympathetic nerves that innervate metastases. Additionally, we will test if adrenergic receptor blockers improve ICB treatment responses in mice exposed to stress. In Aim 3, we will address how metastases changes the electrophysiological properties of PVNCRH neurons, allowing us to identify putative ion channel families altered by metastatic cancer. Our studies will provide mechanistic insights into the maladaptive stress-metastasis feedforward loop and have implications for preventing metastasis from disseminated cancer cells and for treating stage IV cancer. Moreover, we are breaking new ground by showing that the communication between cancer and the brain is bidirectional.
