Journal Article

The Nerve Growth Factor Receptor CD271 Is Crucial to Maintain Tumorigenicity and Stem-Like Properties of Melanoma Cells

Schäfer, Reinhold, Redmer, Torben, Przybilla, Dorothea, Regenbrecht, Christian R. A., Behrens, Diana, Welte, Yvonne, Lehrach, Hans, Fichtner, Iduna, Wruck, Wasco, Yaspo, Marie-Laure

2014

Overview

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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: AC133 Antigen / Analysis / Animals / Antigens / Antigens, CD - biosynthesis / Antigens, CD - genetics / Biology and Life Sciences / Biomarkers, Tumor - biosynthesis / Biomarkers, Tumor - genetics / Cancer / Cell division / Cell Line, Tumor / Cell surface / Colonies / Drug resistance / Epigenetics / Female / Fibroblasts / Gene expression / Gene Knockdown Techniques / Gene set enrichment analysis / Genes / Genomes / Genomic analysis / Genomics / Genotype & phenotype / Glycoproteins - biosynthesis / Glycoproteins - genetics / Growth factors / Heterogeneity / Humans / Laboratories / Male / Markers / Medicine and Health Sciences / Melanoma / Melanoma - genetics / Melanoma - metabolism / Melanoma - pathology / Meta-Analysis as Topic / Metastases / Metastasis / Mice / Mice, Inbred NOD / Neoplasm Proteins - biosynthesis / Neoplasm Proteins - genetics / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Nerve growth factor / Nerve Tissue Proteins - biosynthesis / Nerve Tissue Proteins - genetics / Neural crest / Neural stem cells / Pathology / Peptides - genetics / Properties (attributes) / Receptors, Nerve Growth Factor - biosynthesis / Receptors, Nerve Growth Factor - genetics / Rodents / Sox10 protein / SOXE Transcription Factors - biosynthesis / SOXE Transcription Factors - genetics / Stem cells / Surface markers / Transcription factors / Tumorigenicity / Tumors