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Network-Based Identification of Altered Stem Cell Pluripotency and Calcium Signaling Pathways in Metastatic Melanoma.

ABSTRACT: Malignancy of cancer has been linked to distinct subsets of stem-like cells, the so-called cancer stem cells (CSCs), which persist during treatment and seem to lead to drug-resistant recurrence. Metastatic spread of cancer cells is one of the hallmarks of malignancy and contributes to most human melanoma-related deaths. Recently, overlapping groups of proteins and pathways were shown to regulate stem cell migration and cancer metastasis, raising the question of whether genes/proteins involved in stem cell pluripotency may have important implications when applied to the biology of cancer metastasis. Furthermore, it is well known that ion channels and receptors, particularly those responsible for calcium (Ca2+) signal generation, are critical in determining the cellular fate of stem cells (SCs). In the present study, we searched for evidence of altered stem cell pluripotency and Ca2+ signaling-related genes in the context of melanoma metastasis. We did this by using network analysis of gene expression in tissue biopsies from three different independent datasets of patients. First, we created an in silico network model ("STEMCa" interactome) showing the landscape of interactions between stem cell pluripotency and Ca2+ signaling-related genes/proteins, and demonstrated that around 51% (151 out of 294) of the genes within this model displayed significant changes of expression (False Discovery Rate (FDR), corrected p-value < 0.05) in at least one of the datasets of melanoma metastasis when compared with primary tumor biopsies (controls). Analysis of the properties (degree and betweenness) of the topological network revealed 27 members as the most central hub (HB) and nonhub-bottlenecks (NH-B) among the 294 genes/proteins of the whole interactome. From those representative genes, CTNNB1, GNAQ, GSK3B, GSTP1, MAPK3, PPP1CC, PRKACA, and SMAD4 showed equal up- or downregulation (corrected p-value < 0.05) in at least 2 independent datasets of melanoma metastases samples and PTPN11 showed upregulation (corrected p-value < 0.05) in three of them when compared with control samples. We postulate that altered expression of stem cell pluripotency and Ca2+ signaling pathway-related genes may contribute to the metastatic transformation, with these central members being an optimal candidate group of biomarkers and in silico therapeutic targets for melanoma metastasis, which deserve further investigation.

SUBMITTER: Neves de Oliveira BH

PROVIDER: S-EPMC5872180 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Network-Based Identification of Altered Stem Cell Pluripotency and Calcium Signaling Pathways in Metastatic Melanoma.

Neves de Oliveira Ben-Hur BH Dalmaz Carla C Zeidán-Chuliá Fares F

Medical sciences (Basel, Switzerland) 20180308 1

Malignancy of cancer has been linked to distinct subsets of stem-like cells, the so-called cancer stem cells (CSCs), which persist during treatment and seem to lead to drug-resistant recurrence. Metastatic spread of cancer cells is one of the hallmarks of malignancy and contributes to most human melanoma-related deaths. Recently, overlapping groups of proteins and pathways were shown to regulate stem cell migration and cancer metastasis, raising the question of whether genes/proteins involved in ...[more]

PMID: 29518019

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Project description:Background: Large-scale genomic analyses of patient cohorts have revealed extensive heterogeneity between individual tumors, contributing to treatment failure and drug resistance. In malignant melanoma, heterogeneity is thought to arise as a consequence of the differentiation of melanoma-initiating cells that are defined by cell-surface markers like CD271 or CD133. Results: Here we identified the nerve growth factor receptor (CD271) as a crucial determinant of melanoma cell tumorigenicity, stem-like properties, heterogeneity and plasticity. Stable shRNA mediated knock-down of CD271 in patient-derived melanoma cells abrogated their tumor-initiating and colony-forming capacity. A genome-wide expression profiling and gene-set enrichment analysis revealed novel connections of CD271 with melanoma-associated genes like CD133 and points to a neural crest stem cell (NCSC) signature lost upon CD271 knock-down. In a meta-analysis, we found CD271 linked to the neural crest specifier SOX10 and observed a shared set of 271 differentially regulated genes. To dissect the connection of CD271 and CD133 we analyzed 10 patient-derived melanoma-cell lines for cell-surface expression of both markers compared to established cell lines MeWo and A375. We found CD271+ cells in the majority of cell lines analyzed as well as in a set of 16 different patient-derived melanoma metastases. Strikingly, only 2/12 cell lines harbored a CD133+ sub-set that in addition comprised a fraction of cells of a CD271+/CD133+ phenotype. Those cells were found in the label-retaining fraction and in vitro deduced from CD271+ but not CD271 knock-down cells. Conclusions: Our present study provides a deeper insight into the regulation of melanoma cell properties and points CD271 out as a regulator of several melanoma-associated genes. Further, our data strongly suggest CD271 is a crucial determinant of stem-like properties of melanoma cells like colony-formation and tumorigenicity. For knock-down of CD271 (NGFR), melanoma cells were transfected with 2 µg of each shRNA plasmid; #2: 5’-ACAACCTCATCCCTGTCTATT-3’; #3: 5’-CCCGAGCACATAGA CTCCTTT-3’ and #4: 5’-CCGAGCACATAGACTCCTTTA-3’ or control shRNA (shCtl 5’-GGAATCTCATTCGATGCATAC-3’; all from Quiagen) using Lipofectamine2000 (Invitrogen). Cells were selected with puromycin (10µg/ ml) over a period of two weeks. Whole genome expression profiling of CD271k.d. cells (shRNA#4) and shCtl. cells was performed with three biological replicates. Illumina raw data of BeadChip HumanHT-12V4 platform were summarized via the BeadStudio without normalization and background correction. Follow-up processing was done via the R/Bioconductor environment employing packages lumi, limma and q-value. Data were normalized with quantile normalization. Genes were termed significantly differentially expressed when the average detection p-value of at least one case was < 0.05 the ratio was outside the interval [0.75,1.33], one of the p-values from limma test, Student's t-test, Welch test and Wilcoxon test was < 0.05. At least one of the q-values corresponding to one of these tests < 0.05.

Project description:Prion diseases are transmissible neurodegenerative diseases that arise due to conformational change of normal, cellular prion protein (PrPC) to protease-resistant isofrom (rPrPSc). Deposition of misfolded PrpSc proteins leads to an alteration of many signaling pathways that includes immunological and apoptotic pathways. As a result, this culminates in the dysfunction and death of neuronal cells. Earlier works on transcriptomic studies have revealed some affected pathways, but it is not clear which is (are) the prime network pathway(s) that change during the disease progression and how these pathways are involved in crosstalks with each other from the time of incubation to clinical death. We perform network analysis on large-scale transcriptomic data of differentially expressed genes obtained from whole brain in six different mouse strain-prion strain combination models to determine the pathways involved in prion diseases, and to understand the role of crosstalks in disease propagation. We employ a notion of differential network centrality measures on protein interaction networks to identify the potential biological pathways involved. We also propose a crosstalk ranking method based on dynamic protein interaction networks to identify the core network elements involved in crosstalk with different pathways. We identify 148 DEGs (differentially expressed genes) potentially related to the prion disease progression. Functional association of the identified genes implicates a strong involvement of immunological pathways. We extract a bow-tie structure that is potentially dysregulated in prion disease. We also propose an ODE model for the bow-tie network. Predictions related to diseased condition suggests the downregulation of the core signaling elements (PI3Ks and AKTs) of the bow-tie network. In this work, we show using transcriptomic data that the neuronal dysfunction in prion disease is strongly related to the immunological pathways. We conclude that these immunological pathways occupy influential positions in the PFNs (protein functional networks) that are related to prion disease. Importantly, this functional network involvement is prevalent in all the five different mouse strain-prion strain combinations that we studied. We also conclude that the dysregulation of the core elements of the bow-tie structure, which belongs to PI3K-Akt signaling pathway, leads to dysregulation of the downstream components corresponding to other biological pathways.

Dataset Information

Network-Based Identification of Altered Stem Cell Pluripotency and Calcium Signaling Pathways in Metastatic Melanoma.

Publications

Network-Based Identification of Altered Stem Cell Pluripotency and Calcium Signaling Pathways in Metastatic Melanoma.

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