Our Big Question
How Do Tumor and Host Interact in Response to Stress?
Cancer patients experience intense stress related to diagnosis, recurrence fears, and therapy duration. This stress is associated with higher metastasis risk and poorer survival, highlighting the need to understand stress-driven metastasis mechanisms for effective therapies. Studies in mice reveal stress-induced effects on primary tumor growth, treatment resistance, and metastatic colonization. While stress can enhance cancer cell proliferation, migration, and seeding in distant tissues, the tissue being colonized is not a passive recipient of cancer cell. Instead, the tissue microenvironment must create a pro-metastatic niche supporting disseminated cancer cell growth. Hence, our lab asks this key question: Do stress-triggered host changes impact tumor growth and metastasis?
Our Findings and Hypothesis
Stress-induced Neutrophil Extracellular Traps (NETs) are necessary for tumor progression
Elevated neutrophil-to-lymphocyte ratios, associated with poor prognosis in cancer, are also found in stressed individuals. Our research using well characterized mouse models showed that chronic stress impacts neutrophils, altering lung microenvironments to favor cancer metastasis. This is because stress hormone glucocorticoids induce neutrophil to form Neutrophil Extracellular Traps (NETs), which are meshes of DNA containing enzymes and other proteins and have multiple pro-metastatic roles. Targeting stress-induced NETs with DNase I or targeting neutrophil glucocorticoid receptors (GR) significantly reduces stress-induced metastases in breast and pancreatic cancer models.
Stress-induced glucocorticoids also increase gut permeability, contributing to inflammatory bowel disease (IBD) and colorectal cancer (CRC) progression. Gut permeability during CRC releases immunogenic products into the liver, a common site for CRC metastasis. We found NETs are present in primary CRC and liver metastases samples. Our aim is to understand stress-induced NETs’ response to gut and liver remodeling, impacting cancer therapy efficacy.
Experimental Model System
- Chronic stress mouse model
- AOM/DSS-induced colitis associated colorectal cancer model.
- Orthotopic transplantation model of CRC and liver metastasis.
- Patient-derived xenografts (PDX) model.
Current Projects
Decoding Stress and Cancer: Navigating the “Stressed” Colorectal Tumor Microenvironment
The laboratory is utilizing its discovery of stress-induced NETs and novel mouse models, aiming to better comprehend the effects of systemic chronic stress on the CRC microenvironment. Specifically, we study the interplay between NETs, the immune populations, neuron and microbiota in mouse models of colitis and CRC.
Current ongoing projects are:
- Determine whether and how stress alters the gut homeostasis.
- Evaluate the effects of stress-induced Neutrophil Extracellular Traps (NETs) on the microenvironment of colorectal cancer (CRC) and its liver metastasis.
- Determine how stress-induced locoregional neuron-tumor interactions affect CRC progression.