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 Ca(2+)-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.
Highlights
Microenvironmental signal cues, to which melanoma cells themselves contribute, constantly shape the properties of melanoma through dynamic switching of transcriptional programs [1, 2]
The analysis was based on a limited number of samples, the data was found to be consistent across two separate models in different host species
The brain-specific signature identified in melanoma cells that metastasized to the brain, showed that these cells acquired neuron-like characteristics
Summary
Microenvironmental signal cues, to which melanoma cells themselves contribute, constantly shape the properties of melanoma through dynamic switching of transcriptional programs [1, 2]. Gene expression profiling studies have previously revealed the presence of two major signatures in melanoma, which distinguish two discrete states of differentiation; an invasive, slow-cycling mesenchymal-cell like phenotype, and a differentiated phenotype intrinsic to melanoma that is highly proliferative [1]. The expression of the invasive signature, driven by Wnt-signaling and TGFβ sensitive genes, has been found to be inversely correlated with the proliferative signature, driven by the MITF transcription factor. Melanomas and neurons share a common embryonal origin (neural crest derived), and the revival of a neuron progenitor phenotype may explain a “homing” phenomenon, and the frequent involvement of CNS metastasis in melanoma [5]. The molecular factors reported to be implicated include VEGF-A [6], STAT3 [7], p75 and neurotrophins [8, 9], transferrin [10], TGFβ [11] and endothelin receptor B (EDNRB) [12]
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