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

Nygaard V, Prasmickaite L, Vasiliauskaite K, Clancy T, Hovig E - Oncoscience (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0310, Norway.

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.

No MeSH data available.


Related in: MedlinePlus

Protein-protein interaction network generated from genes with differential expression during metastatic growth in the brain(A) Protein-protein interaction (PPI) network based on differentially expressed genes between intermediate and late growth phase. The network was constructed from an integrated set of protein interaction database in combination with a gene ontology (GO) analysis). Lines indicate physical interaction between the proteins (circles). The outline of the circles indicate up (red)- or down (green)-regulated gene expression. The members of the network have been color-coded according to their association with the following biological functions; neurogenesis (blue), invasion (yellow) and survival (purple). (B) Reduced complexity network based on the central nodes in (A). The nodes shared common involvement in biological functions (spheres).
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Figure 3: Protein-protein interaction network generated from genes with differential expression during metastatic growth in the brain(A) Protein-protein interaction (PPI) network based on differentially expressed genes between intermediate and late growth phase. The network was constructed from an integrated set of protein interaction database in combination with a gene ontology (GO) analysis). Lines indicate physical interaction between the proteins (circles). The outline of the circles indicate up (red)- or down (green)-regulated gene expression. The members of the network have been color-coded according to their association with the following biological functions; neurogenesis (blue), invasion (yellow) and survival (purple). (B) Reduced complexity network based on the central nodes in (A). The nodes shared common involvement in biological functions (spheres).

Mentions: Using SAM analysis, we identified 697 differentially expressed genes (FC=±2) between intermediate (n=2) vs. late growth phase samples (n=4) (585 up-regulated/112 down-regulated, Supporting Information Dataset S2-S3). We generated a protein-protein interaction (PPI) network based on these 697 genes in combination with a gene ontology (GO) analysis in order to focus on central molecules and processes in our data set (Fig 3A). The PPI network was constructed from an integrated set of protein interaction databases whereby each interaction represented a known physical binding between two proteins. Six of the eleven central nodes were associated with all three investigated GO terms (neurogenesis, invasion and survival) indicating pleiotropic effects of these genes. The central nodes were re-drawn and key biological functions were distributed to best fit the central nodes and their associated node members (Fig. 3B). Notably, central genes (APP, MBP, and APOE) in the network are implicated in neuro-pathological disorders and metabolic disease, but have not previously been assigned significance in brain metastasis. The key biological functions including neuron development, neuro-inflammation, motility and survival, summarize the identified processes involved in melanoma adaptation and growth in the brain microenvironment based on the gene expression data obtained from our model and described below.


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

Nygaard V, Prasmickaite L, Vasiliauskaite K, Clancy T, Hovig E - Oncoscience (2014)

Protein-protein interaction network generated from genes with differential expression during metastatic growth in the brain(A) Protein-protein interaction (PPI) network based on differentially expressed genes between intermediate and late growth phase. The network was constructed from an integrated set of protein interaction database in combination with a gene ontology (GO) analysis). Lines indicate physical interaction between the proteins (circles). The outline of the circles indicate up (red)- or down (green)-regulated gene expression. The members of the network have been color-coded according to their association with the following biological functions; neurogenesis (blue), invasion (yellow) and survival (purple). (B) Reduced complexity network based on the central nodes in (A). The nodes shared common involvement in biological functions (spheres).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4295759&req=5

Figure 3: Protein-protein interaction network generated from genes with differential expression during metastatic growth in the brain(A) Protein-protein interaction (PPI) network based on differentially expressed genes between intermediate and late growth phase. The network was constructed from an integrated set of protein interaction database in combination with a gene ontology (GO) analysis). Lines indicate physical interaction between the proteins (circles). The outline of the circles indicate up (red)- or down (green)-regulated gene expression. The members of the network have been color-coded according to their association with the following biological functions; neurogenesis (blue), invasion (yellow) and survival (purple). (B) Reduced complexity network based on the central nodes in (A). The nodes shared common involvement in biological functions (spheres).
Mentions: Using SAM analysis, we identified 697 differentially expressed genes (FC=±2) between intermediate (n=2) vs. late growth phase samples (n=4) (585 up-regulated/112 down-regulated, Supporting Information Dataset S2-S3). We generated a protein-protein interaction (PPI) network based on these 697 genes in combination with a gene ontology (GO) analysis in order to focus on central molecules and processes in our data set (Fig 3A). The PPI network was constructed from an integrated set of protein interaction databases whereby each interaction represented a known physical binding between two proteins. Six of the eleven central nodes were associated with all three investigated GO terms (neurogenesis, invasion and survival) indicating pleiotropic effects of these genes. The central nodes were re-drawn and key biological functions were distributed to best fit the central nodes and their associated node members (Fig. 3B). Notably, central genes (APP, MBP, and APOE) in the network are implicated in neuro-pathological disorders and metabolic disease, but have not previously been assigned significance in brain metastasis. The key biological functions including neuron development, neuro-inflammation, motility and survival, summarize the identified processes involved in melanoma adaptation and growth in the brain microenvironment based on the gene expression data obtained from our model and described below.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0310, Norway.

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.

No MeSH data available.


Related in: MedlinePlus