Melanoma brain colonization involves the emergence of a brain-adaptive phenotype

Abstract

The brain offers a unique microenvironment that plays an important role in the establishment and progression of metastasis. However, the molecular determinants that promote development of melanoma brain metastases are largely unknown. Utilizing two species of immune-compromised animals, with in vivo cultivated metastatic tissues along with their corresponding host tissues in a metastasis model, we here identify molecular events associated with melanoma brain metastases. We find that the transcriptional changes in the melanoma cells, as induced by the brain-microenvironment in both host species, reveal the opportunistic nature of melanoma in this biological context in rewiring the molecular framework of key molecular players with their associated biological processes. Specifically, we identify the existence of a neuron-like melanoma phenotype, which includes synaptic characteristics and a neurotransmission-like circuit involving glutamate. Regulation of gene transcription and neuron-like plasticity by Ca2+-dependent signaling appear to occur through glutamate receptor activation. The brain-adaptive phenotype was found as more prominent in the early metastatic growth phases compared to a later phase, emphasizing a temporal requirement of critical events in the successful colonization of the brain. Analysis of the host tissue uncovered a cooperative inflammatory microenvironment formed by activated host cells that permitted melanoma growth at the expense of the host organism. Combined experimental and computational approaches clearly highlighted genes and signaling pathways being shared with neurodegenerative diseases. Importantly, the identification of essential molecular networks that operate to promote the brain-adaptive phenotype is of clinical relevance, as they represent leads to urgently needed therapeutic targets.

Molecular insights into melanoma brain metastases

“…In an extensive microarray study of lung, breast, and melanoma xenografts at different metastatic sites, Park and colleagues observed epigenetically regulated transcriptional reprogramming of tumor cells in the brain to a more neuronal phenotype that was partly induced by astrocytes . Similar results were reported by Nygaard et al, who observed a neuron‐like phenotype of melanoma cells implanted into the brain, especially in the early phase of metastatic growth . The acquisition of a neuronal phenotype of tumor cells because of transcriptional changes may be another mechanism of immune evasion.…”

Metabolic advantages and vulnerabilities in brain metastases

“…Melanoma is often associated with BRAF mutations, which drive malignancy and have been targeted by successful therapeutics such as Vemurafenib and Dabrafenib (59). Melanoma cells that exhibit neuronal-like phenotypes such as glutamate and calcium signaling during early metastatic growth possess a brain-colonizing advantage (60). In addition, loss of claudin 1, a factor in tight junctions that interacts with endothelial cells in the brain, promotes melanoma-to-brain metastasis (61).…”

Metabolic reprogramming supports the invasive phenotype in malignant melanoma

“…Two melanoma cell lines, Melmet 1 and Melmet 5, representing the highly invasive and poorly invasive phenotype, respectively [30], were utilized. By use of a transwell chamber assay, we showed that both migration and invasion were stimulated by S100A4 in the poorly motile Melmet 5 cells, with a fold increase of 1.8 and 2.4, respectively (Fig.…”