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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

Signal intensity heatmap of the top 30 differentially expressed genes derived from a direct comparison between the mixed-species sample (early brain metastatic growth, marked with ∆) versus a normal mouse brain (marked with Ѳ) hybridized to a human-specific beadarrayColumns represent samples and rows show gene expression levels. Comparison against pure tumor samples indicated that the expression level for the majority of the 30 genes was specific for the early growth sample while a minority could be interpreted as diluted tumor-specific signal.
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Figure 6: Signal intensity heatmap of the top 30 differentially expressed genes derived from a direct comparison between the mixed-species sample (early brain metastatic growth, marked with ∆) versus a normal mouse brain (marked with Ѳ) hybridized to a human-specific beadarrayColumns represent samples and rows show gene expression levels. Comparison against pure tumor samples indicated that the expression level for the majority of the 30 genes was specific for the early growth sample while a minority could be interpreted as diluted tumor-specific signal.

Mentions: From the gene expression data, we extracted genes with at least a 2-fold higher expression level in the mixed-species sample (MM5/mouse, representing early growth phase), compared to the normal mouse brain sample. The up-regulated genes (3848) were interpreted to belong to the categories of either tumor-specific genes, or cross-hybridizing genes in the diseased mouse brain with altered expression compared to the normal, healthy mouse brain (Supporting Information Dataset S4). Signal intensity alignment of the top 30 up-regulated genes was inspected across all samples so as to evaluate which genes could potentially be associated with early growth of melanoma in the brain (Fig. 6]. The top 5 gene rows appeared to be genes with a diluted tumor-specific signal, and thus not specific to either early growth phase or organ. The genes reported below, however, showed exclusive high expression in the mixed-species sample. The most differentially expressed gene, NUS1 (Nogo-B receptor) (13.8-fold), is involved in angiogenesis and migration. Energy sensing and metabolism were related to the genes GLS2, FNIP1, PHKB, PPARD, GCLC and NUAK2. Neuregulin growth factor NRG2 (12.3 fold), a ligand for the ERBB receptor family was also among the top 30 genes. The main results of significantly associated biological functions and canonical pathways for the mapped genes in the dataset (2412/3848) are reported in Supporting Information Table S3. Highly ranked annotated functions included processes such as “growth of neurites”, “metastasis of tumor” and “development of fetal membranes”. “EIF2 Signaling” and “Ephrin Receptor Signaling” were highly ranked in the list of significant canonical pathways reflecting stress, immune response and cell-cell interactions. The identification of RAF1 as a predicted activated upstream regulator was not surprising considering this analysis involved a comparison between neoplastic and normal tissue. The output from the upstream regulator analysis also included activated status for EGR2 and HNF4A. HNF4A, a transcription factor involved in lipid metabolism, possesses known regulatory functions towards 246 gene targets up-regulated in the early growth sample. Several microRNAs were identified as inhibited upstream regulators. DICER1, a key component in the miRNA processing machinery was also assigned to inhibited status, albeit not within the significance cut-off score. Down-regulated genes in the mixed-species sample were not pursued due to the likelihood of confounding factors. Briefly, a large number of down-regulated genes were associated with cell death and cellular metabolism. Pathway analysis showed associations to gliosis and astrocytosis.


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

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

Signal intensity heatmap of the top 30 differentially expressed genes derived from a direct comparison between the mixed-species sample (early brain metastatic growth, marked with ∆) versus a normal mouse brain (marked with Ѳ) hybridized to a human-specific beadarrayColumns represent samples and rows show gene expression levels. Comparison against pure tumor samples indicated that the expression level for the majority of the 30 genes was specific for the early growth sample while a minority could be interpreted as diluted tumor-specific signal.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Signal intensity heatmap of the top 30 differentially expressed genes derived from a direct comparison between the mixed-species sample (early brain metastatic growth, marked with ∆) versus a normal mouse brain (marked with Ѳ) hybridized to a human-specific beadarrayColumns represent samples and rows show gene expression levels. Comparison against pure tumor samples indicated that the expression level for the majority of the 30 genes was specific for the early growth sample while a minority could be interpreted as diluted tumor-specific signal.
Mentions: From the gene expression data, we extracted genes with at least a 2-fold higher expression level in the mixed-species sample (MM5/mouse, representing early growth phase), compared to the normal mouse brain sample. The up-regulated genes (3848) were interpreted to belong to the categories of either tumor-specific genes, or cross-hybridizing genes in the diseased mouse brain with altered expression compared to the normal, healthy mouse brain (Supporting Information Dataset S4). Signal intensity alignment of the top 30 up-regulated genes was inspected across all samples so as to evaluate which genes could potentially be associated with early growth of melanoma in the brain (Fig. 6]. The top 5 gene rows appeared to be genes with a diluted tumor-specific signal, and thus not specific to either early growth phase or organ. The genes reported below, however, showed exclusive high expression in the mixed-species sample. The most differentially expressed gene, NUS1 (Nogo-B receptor) (13.8-fold), is involved in angiogenesis and migration. Energy sensing and metabolism were related to the genes GLS2, FNIP1, PHKB, PPARD, GCLC and NUAK2. Neuregulin growth factor NRG2 (12.3 fold), a ligand for the ERBB receptor family was also among the top 30 genes. The main results of significantly associated biological functions and canonical pathways for the mapped genes in the dataset (2412/3848) are reported in Supporting Information Table S3. Highly ranked annotated functions included processes such as “growth of neurites”, “metastasis of tumor” and “development of fetal membranes”. “EIF2 Signaling” and “Ephrin Receptor Signaling” were highly ranked in the list of significant canonical pathways reflecting stress, immune response and cell-cell interactions. The identification of RAF1 as a predicted activated upstream regulator was not surprising considering this analysis involved a comparison between neoplastic and normal tissue. The output from the upstream regulator analysis also included activated status for EGR2 and HNF4A. HNF4A, a transcription factor involved in lipid metabolism, possesses known regulatory functions towards 246 gene targets up-regulated in the early growth sample. Several microRNAs were identified as inhibited upstream regulators. DICER1, a key component in the miRNA processing machinery was also assigned to inhibited status, albeit not within the significance cut-off score. Down-regulated genes in the mixed-species sample were not pursued due to the likelihood of confounding factors. Briefly, a large number of down-regulated genes were associated with cell death and cellular metabolism. Pathway analysis showed associations to gliosis and astrocytosis.

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