Astrogliosis is Instigated in a Novel Mouse Model of Spontaneous Melanoma Brain Metastasis

Malignant melanoma is the deadliest of all skin cancers. Melanoma frequently metastasizes to the brain, resulting in dismal survival. One of the major obstacles for characterizing mechanisms of brain metastasis is the lack of tractable pre-clinical models. Utilizing a Ret-melanoma-derived cell line we have established and characterized a novel mouse model of spontaneous melanoma brain metastasis in immunocompetent mice that gives rise to both micro- and macro- metastases. We show that 3-4 months after surgical excision of primary tumors, 50% of the mice develop brain macrometastases. By utilizing a unique ex-vivo modeling system we detected brain micrometastases in 50-60% of the mice and quantified the metastatic load. Moreover, we established tools for intravital diagnosis of brain micrometastases by analyzing blood and cerebrospinal fluid (CSF). We next demonstrated that astrogliosis is instigated early during metastases formation: astrocytes were recruited to metastatic brain lesions, and paracrine signaling by melanoma cells activated a ‘wound healing program’ in astrocytes, reflected in up-regulation of Cxcl10, Timp1, Lcn2, Serpine1 and Serpina3n. Finally, we show that co-injection of astrocytes with melanoma cells intra-cranially resulted in a striking increase of tumor volume. Our findings suggest that astrogliosis, physiologically instigated as a brain tissue damage response, is hijacked by tumor cells to support metastatic growth. This novel model enables the integrative study of tumor cells, immune cells and brain stromal cells and can be utilized as a platform for pre-clinical trials. Since brain metastases are currently incurable, elucidating molecular mechanisms operative in early metastatic growth and signaling pathways that govern metastatic dormancy is the key to developing new therapeutic approaches that may prevent brain metastatic relapse.