The Chen Laboratory
The Chen laboratory studies cancer metastasis, the spread of cancer from primary tumor site to distal organs, which is the cause of 90% of deaths from cancer. The brain is one of the common metastasis locations in breast cancer. Therapeutic strategies, including novel chemotherapies and targeted inhibitors, have limited efficacy in brain metastatic lesions. As a consequence, the incidence of brain metastases has increased in recently years, especially in triple-negative and HER2-positive breast cancer patients. Metastatic outgrowth requires the complex interplay between cancer cells and the microenvironment in distal organs.
Our lab focuses on this crosstalk to reveal mechanisms that mediate cancer survival/growth in distal organs. We are particularly interested in the metastatic outgrowth in the unique brain microenvironment. For example, astrocytes (the stromal cells that only exist in the brain) densely infiltrate into brain metastatic lesions. Notably, astrocytes have dual functions - killing and protecting - in the invaded cancer cells. We are taking a multidisciplinary approach, spanning molecular and biochemical analyses combined with sophisticated in vivo imaging, with the ultimate goal of dissecting the dynamic cancer cell-astrocyte interactions both temporally and spatially. The mechanistic insights into the metastatic process will facilitate the development of more effective therapies.
Maria Cecilia Oliveira Ferreira Nunes
Metastasis presents a major threat to the lives of cancer patients. Brain metastasis is becoming a significant clinical problem and its incidence is rising. This is largely attributable to the fact that current therapies, which are effective in controlling extracranial metastasis that prolong patient survival, are ineffective in controlling metastatic disease of the brain. Our goal is to elucidate the underlying mechanisms that mediate metastasis and therapeutic resistance in the brain.
Emerging evidence indicates that metastatic outgrowth at distal organs requires the complex interplay between cancer cells and the stromal cells, a process commonly referred to as “seed and soil hypothesis”. The ‘soil’, brain, is composed of specific cell types: functional neurons and supporting glial cells. This unique brain microenvironment not only decides the outgrowth of metastatic cancer cells, but also contributes to therapy resistance. Meanwhile, the ‘seed’, invaded cancer cells, modifies the surrounding brain stromal cells. Thus, the lab is applying innovated approaches to dissect the crosstalk between cancer cells and the brain microenvironment at various stages of metastatic development, to identify potential targets to prevent and/or treat brain metastasis.
Brain metastatic cells have higher expression of protocadherin 7 (PCDH7) and the gap junction component connexin 43 (Cx43). PCDH7 interacts with Cx43 hemi-channels to assemble carcinoma-astrocyte gap junctions. Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells employ these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and the production of inflammatory cytokines IFNα and TNFα. As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, which support tumor growth and chemoresistance.