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CD271 is an imperfect marker for melanoma initiating cells.

ABSTRACT: Understanding the molecular and cellular processes underlying melanoma plasticity and heterogeneity is of paramount importance to improve the efficiency of current treatment and to overcome resistance to chemotherapy drugs. The notion of plasticity and heterogeneity implies the existence of melanoma cell populations with different phenotypic and tumorigenic properties. Using melanoma cell lines and melanoma cells freshly isolated from patient biopsies, we investigated the relationship between ABCB5+, CD271+ and low-MITF, expressing populations that were reported to display melanoma initiating cell properties. Here, we showed that ABCB5+ and CD271+ populations poorly overlap. However, we found that the CD271+ population is enriched in low-MITF cells and expresses a higher level of stemness genes, such as OCT4, NANOG and NES. These features could explain the increased tumorigenicity of the CD271+ cells. The rapid conversion of CD271+ to CD271- cells in vitro demonstrates the plasticity ability of melanoma cells. Finally, we observed that the transient slow-growing population contains only CD271+ cells that are highly tumorigenic. However, the fast growing/CD271+ population exhibits a poor tumorigenic ability. Taking together, our data show that CD271 is an imperfect marker for melanoma initiating cells, but may be useful to identify melanoma cells with an increased stemness and tumorigenic potential.

SUBMITTER: Cheli Y

PROVIDER: S-EPMC4170612 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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CD271 is an imperfect marker for melanoma initiating cells.

Cheli Yann Y Bonnazi Vanessa F VF Jacquel Arnaud A Allegra Maryline M De Donatis Gian Marco GM Bahadoran Philippe P Bertolotto Corine C Ballotti Robert R

Oncotarget 20140701 14

Understanding the molecular and cellular processes underlying melanoma plasticity and heterogeneity is of paramount importance to improve the efficiency of current treatment and to overcome resistance to chemotherapy drugs. The notion of plasticity and heterogeneity implies the existence of melanoma cell populations with different phenotypic and tumorigenic properties. Using melanoma cell lines and melanoma cells freshly isolated from patient biopsies, we investigated the relationship between AB ...[more]

PMID: 25105565

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Project description:Several lines of evidence have suggested that stemness and acquired resistance to targeted inhibitors or chemotherapeutics are mechanistically linked. Here we observed high cell surface and total levels of nerve growth factor receptor/CD271, a marker of melanoma-initiating cells, in sub-populations of chemoresistant cell lines. CD271 expression was increased in drug-sensitive cells but not resistant cells in response to DNA-damaging chemotherapeutics etoposide, fotemustine and cisplatin. Comparative analysis of melanoma cells engineered to stably express CD271 or a targeting short hairpin RNA by expression profiling provided numerous genes regulated in a CD271-dependent manner. In-depth analysis of CD271-responsive genes uncovered the association of CD271 with regulation of DNA repair components. In addition, gene set enrichment analysis revealed enrichment of CD271-responsive genes in drug-resistant cells, among them DNA repair components. Moreover, our comparative screen identified the fibroblast growth factor 13 (FGF13) as a target of CD271, highly expressed in chemoresistant cells. Further we show that levels of CD271 determine drug response. Knock-down of CD271 in fotemustine-resistant cells decreased expression of FGF13 and at least partly restored sensitivity to fotemustine. Together, we demonstrate that expression of CD271 is responsible for genes associated with DNA repair and drug response. Further, we identified 110 CD271-responsive genes predominantly expressed in melanoma metastases, among them were NEK2, TOP2A and RAD51AP1 as potential drivers of melanoma metastasis. In addition, we provide mechanistic insight in the regulation of CD271 in response to drugs. We found that CD271 is potentially regulated by p53 and in turn is needed for a proper p53-dependent response to DNA-damaging drugs. In summary, we provide for the first time insight in a CD271-associated signaling network connecting CD271 with DNA repair, drug response and metastasis.

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.

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CD271 is an imperfect marker for melanoma initiating cells.

Publications

CD271 is an imperfect marker for melanoma initiating cells.

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