Metastases to the CNS are ten times more common than primary brain tumors. Despite this, brain metastases are far less commonly the subject of laboratory or clinical investigation. As a result, current clinical management affords limited disease control. Improved mechanistic understanding of CNS metastases and novel rational therapeutic strategies are urgently needed.
The CNS encompasses two distinct microenvironments: the densely cellular parenchyma and the cerebrospinal fluid (CSF)-filled leptomeninges. Each of these microenvironments is isolated separately from the systemic circulation and each selects for distinct molecular characteristics in metastatic cancer cells.
The lab employs multiple, complementary orthogonal strategies to dissect cancer cell micro-environmental interactions. These interactions provide a roadmap of vulnerabilities that may be exploited therapeutically.
Metastasis to the leptomeningeal space (LM) may occur from any primary cancer. Of solid tumors, LM results most frequently from breast, lung, and melanoma primaries. Unfortunately, the molecular mechanisms that underlie LM remain largely obscure. Using an iterative in vivo selection strategy, we are able to pose basic questions regarding cancer cell entry into the leptomeninges and cancer cell growth within this space. To answer these questions, we exploit these mouse models alongside in vitro models and analysis of human biomaterial.
Cancer Cell-Choroid Plexus Interactions
We have recently found that C3aR activation renders the choroid plexus selectively permeable, altering CSF composition to support cancer cell growth. We are currently investigating the temporal and chemical limits of this permeability. In addition, we are exploring the possible therapeutic role of C3aR activation. Our previous work demonstrates that C3aR antagonists inhibit cancer cell growth within the leptomeninges. How pharmacologic manipulation of C3aR activity might applied to LM treatment is an area of active investigation.
Molecular Interrogation of CNS Metastasis
We are undertaking comprehensive molecular interrogation of clinical samples from CNS metastasis. Querying these samples from DNA, RNA, protein, and small-molecule-based approaches, we will generate high-resolution, multimodality pictures of the molecular call and response occurring between cancer cells and their microenvironment.