Abstract | 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 confirmed that the nerve growth factor receptor ( CD271) is a crucial determinant of tumorigenicity, stem-like properties, heterogeneity and plasticity in melanoma cells. 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 have determined a shared set of 271 differentially regulated genes, linking CD271 to SOX10, a marker that specifies the neural crest. To dissect the connection of CD271 and CD133 we have analyzed 10 patient-derived melanoma-cell strains for cell-surface expression of both markers compared to established cell lines MeWo and A375. We found CD271+ cells in the majority of cell strains analyzed as well as in a set of 16 different patient-derived melanoma metastases. Strikingly, only 2/12 cell strains 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 that CD271 is a crucial determinant of stem-like properties of melanoma cells like colony-formation and tumorigenicity.
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Authors | Torben Redmer, Yvonne Welte, Diana Behrens, Iduna Fichtner, Dorothea Przybilla, Wasco Wruck, Marie-Laure Yaspo, Hans Lehrach, Reinhold Schäfer, Christian R A Regenbrecht |
Journal | PloS one
(PLoS One)
Vol. 9
Issue 5
Pg. e92596
( 2014)
ISSN: 1932-6203 [Electronic] United States |
PMID | 24799129
(Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- AC133 Antigen
- Antigens, CD
- Biomarkers, Tumor
- Glycoproteins
- NGFR protein, human
- Neoplasm Proteins
- Nerve Tissue Proteins
- PROM1 protein, human
- Peptides
- Prom1 protein, mouse
- Receptors, Nerve Growth Factor
- SOX10 protein, human
- SOXE Transcription Factors
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Topics |
- AC133 Antigen
- Animals
- Antigens, CD
(biosynthesis, genetics)
- Biomarkers, Tumor
(biosynthesis, genetics)
- Cell Line, Tumor
- Female
- Gene Knockdown Techniques
- Glycoproteins
(biosynthesis, genetics)
- Humans
- Male
- Melanoma
(genetics, metabolism, pathology)
- Meta-Analysis as Topic
- Mice
- Mice, Inbred NOD
- Neoplasm Proteins
(biosynthesis, genetics)
- Neoplastic Stem Cells
(metabolism, pathology)
- Nerve Tissue Proteins
(biosynthesis, genetics)
- Peptides
(genetics)
- Receptors, Nerve Growth Factor
(biosynthesis, genetics)
- SOXE Transcription Factors
(biosynthesis, genetics)
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