Interrogating Type I Interferon signaling in breast cancer brain metastasis

PROJECT SUMMARY The brain is one of the common organs for breast cancer recurrence. Breast cancer brain metastasis is increasingly becoming a significant clinical problem due to its rising incidence and limited efficacy of existing systemic therapies. Metastasis is the consequence of favorable interactions between the invaded cancer cells

and the microenvironment in the distal organ. To cancer cells, the brain has the most unique microenvironment since the stromal cells in the brain do not exist in any other organs. This explains why therapeutic strategies, which efficiently diminish primary and non-brain metastatic breast tumors, are

ineffective in controlling the established brain lesions. Our current work aims to understand the unique brain metastasis microenvironment and delineate how it facilitates metastatic outgrowth. Type I interferon (IFN) signaling is a well-recognized anti-tumor pathway. However, experiments from our animal models show that

type I response in astrocytes, the unique brain stromal cells, has a pro-metastatic effect in the brain. Based on these findings, we will further address the following questions: 1) Define the underlying mechanisms in how the type I IFN response in astrocytes mediates brain metastasis. We will test the hypothesis that the

activated IFN response in astrocytes helps the recruitment of specific immune cells into the brain lesions. 2) Validate the type I IFN activation at different stages of brain metastasis. We will apply the top-notch imaging technique in our mouse models to directly visualize cellular and molecular changes as they occur in real-time,

and validate these observations in clinical samples. 3) Investigate the therapeutic effect of inhibition of immune cell recruitment on brain metastasis. We will not only identify the druggable targets, but also optimize the therapeutic windows in our pre-clinical mouse models. Overall, our idea is that once we know how the

brain microenvironment helps cancer growth in the brain, we can focus our efforts on stopping it. Our research proposal will yield real and actionable targets on brain microenvironment, instead of on cancer cells, to treat brain metastasis. More importantly, our studies on tracking the dynamic changes during brain metastatic

process will help identify the optimal therapeutic strategies to effectively treat brain metastasis and minimize potential side effect.