A human melanoma xenograft model in nude mice was previously generated in our lab. At our disposal are cultured variants of brain (macro) metastases, brain micro-metastases which disseminated spontaneously to the brain from cutaneous tumors. These cells are dormant when residing in the brain metastatic microenvironment. All these variants originated in the same melanoma thus sharing a common genetic origin. Genetic, proteomic and transcriptomic differences between these variants can therefore be attributed to their differential malignancy phenotype and microenvironmental influence. The variants had the V600 mutation of B-RAF.
Previous studies from our lab characterized a molecular profile associated with melanoma brain metastasis and demonstrated that factors derived from the brain microenvironment have profound effects on the phenotype of melanoma cells. The present study expands these studies.
The BRAFV600E mutation is involved in melanoma progression. The majority of patients treated with Vemurafenib show shrinkage of tumor lesions, although the disease relapse is quickly manifested in most of them.
The specific aims of the present study are:
1. Obtain a deeper insight of the interaction of brain melanoma macro and micro metastases with the metastatic brain microenvironment
2. Characterize molecular and functional differences between melanoma variants that are resistant to Vemurafenib and their control Vemurafenib-sensitive counterparts
The results showed that the in vitro interaction of brain-metastasizing melanoma cells with brain-derived factors altered the gene expression profile of brain macro and micro-metastatic melanoma cells. Brain-derived factors but not lung-derived factors induced cell death of macro- and micro-metastatic cells.
The malignancy phenotype of Vemurafenib-resistant cells was significantly increased compared to control cells. Among the molecular changes occurring in Vemurafenib-resistant cells is a highly significant up-regulation of the chemokine receptor CCR4 whose ligands expressed in brain tissue.
Of interest is the fact that Vemurafenib-resistant cells are fully sensitive to the cytotoxicity mediated by brain-derived factors.
These results support the notion that metastasis depends on continuous reciprocal interactions between cancer cells and their surrounding microenvironment.
This study was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (Needham, MA, USA).
