title: The nerve growth factor receptor CD271 is crucial to maintain tumorigenicity and stem-like properties of melanoma cells.
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.
authors.affiliation: Institute for Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Torben
authors.initials: T
authors.lastname: Redmer
authors.affiliation: Institute of Pathology - University Hospital Berlin, Berlin, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Welte
authors.affiliation: Experimental Pharmacology & Oncology Berlin-Buch GmbH, Berlin, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Behrens
authors.affiliation: Experimental Pharmacology & Oncology Berlin-Buch GmbH, Berlin, Germany.
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
authors.affiliation: Institute of Pathology - University Hospital Berlin, Berlin, Germany; Comprehensive Cancer Center Charité - University Hospital Berlin, Berlin, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Przybilla
authors.affiliation: Institute of Pathology - University Hospital Berlin, Berlin, Germany; Laboratory of Functional Genomics (LFGC) - University Hospital Berlin, Berlin, Germany.
authors.forename: Wasco
authors.initials: W
authors.lastname: Wruck
authors.affiliation: Max-Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Yaspo
authors.affiliation: Max-Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.affiliation: Institute of Pathology - University Hospital Berlin, Berlin, Germany; Comprehensive Cancer Center Charité - University Hospital Berlin, Berlin, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schäfer
authors.affiliation: Institute of Pathology - University Hospital Berlin, Berlin, Germany; Laboratory of Functional Genomics (LFGC) - University Hospital Berlin, Berlin, Germany; Comprehensive Cancer Center Charité - University Hospital Berlin, Berlin, Germany.
authors.forename: Christian R A
authors.initials: CR
authors.lastname: Regenbrecht
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015201:Meta-Analysis as Topic; D051379:Mice; D016688:Mice, Inbred NOD; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D010455:Peptides / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D055757:SOXE Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D006023:Glycoproteins; C484065:NGFR protein, human; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D017475:Receptors, Nerve Growth Factor; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors