Abstract
There is critical need to study leptomeningeal metastasis (LM), a fatal complication of cancer accompanied by severe neurological deficits. LM occurs when cancer cells enter the leptomeninges, float in the cerebrospinal fluid (CSF), and adhere to the surface of the brain and spinal cord. Understanding the molecular basis of LM requires reliable models of the disease that can recapitulate the complex microenvironment that supports LM cell growth. Here, we define a protocol for iterative in vivo selection of cancer cells competent to colonize the leptomeninges (LeptoM cells) from a larger population of primary tumor cells that stably express GFP and luciferase. We use these LeptoM cells to establish tractable models of leptomeningeal disease in both syngeneic and xenograft mice. With these models, we modulate disease severity and capture snapshots of hallmark LM characteristics over time. We demonstrate the fidelity of these mouse models to human disease in several dimensions: 1. Biochemically, through CSF proteomics and metabolomics; 2. Immunologically, via flow cytometry and cytokine profiling; 3. Transcriptionally through RNA sequencing; and 4. Neurologically by accumulation of neurological signs. They are freely available to the academic community. These models provide robust, reproducible tools for discovery and mechanistic dissection. They will enable identification of critical disease mechanisms, and assays of novel treatment modalities against LM.