<scp>ZEB</scp>
            1‐mediated melanoma cell plasticity enhances resistance to
            <scp>MAPK</scp>
            inhibitors

Richard, G; Dalle, S.; Monet, Michaël; Ligier, Maud; Boespflug, Amélie; Pommier, Roxane M.; Fouchardière, Arnaud de la; Perier‐Muzet, Marie; Depaepe, L.; Barnault, Romain; Tondeur, G; Ansieau, Stéphane; Thomas, Emilie; Bertolotto, Corine; Ballotti, Robert; Mourah, Samia; Battistella, Maxime; Lebbe, Célèste; Thomas, Luc; Puisieux, Alain; Caramel, Julie

doi:10.15252/emmm.201505971

Cited by 110 publications

(135 citation statements)

References 57 publications

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“…ZEB1 represses miR-200 as well as miR-203, which can also suppress stemness hallmarks (27). The level of ZEB1 is also upregulated in melanoma cells with acquired resistance and in biopsies from relapsed patients during treatment (28). Additionally, patients with a mucinous and clear-cell histology generally showed a very low response rate to platinum-based chemotherapy, leading to intrinsic chemoresistance (29,30).…”

Section: Discussionmentioning

confidence: 99%

Impact of positive ZEB1 expression in patients with epithelial ovarian carcinoma as an oncologic outcome-predicting indicator

et al. 2017

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Abstract. Several previous studies have revealed that the expression of zinc finger E-box binding homeobox 1 (ZEB1) in solid malignancies has an important significance on the clinical outcome of patients. However, the association between ZEB1 expression and survival in patients with epithelial ovarian carcinoma (EOC) remains unclear. The objective of the present study was to examine the extent of ZEB1 expression in EOC using immunohistochemical staining and investigate its association with patient outcome. A total of 40 patients with EOC initially treated with cytoreductive surgery and systematic chemotherapy were enrolled. ZEB1 expression was immunohistochemically categorized as negative, weak, moderate and strong according to the size of the staining area, and intensity. Subsequently, the associations between ZEB1 expression and recurrence/progression-free survival (RFS) rate were examined. The median age of patients in the current study was 54 years old (range, 22-72 years old). Among these patients, 15 (37.5%) exhibited International Federation of Gynecology and Obstetrics stage I disease, and 10 (25.0%), 13 (32.5%), and 2 (5%) had stage II, III, and IV disease, respectively. No patients with negative expression of ZEB1 experienced recurrence. In addition, ZEB1 expression was identified to be a significant predictor of a poorer RFS rate compared with negative expression (negative vs. weak, moderate and strong, P= 0.0126). Furthermore, multivariate analyses revealed that moderate and strong ZEB1 expression levels were significant prognostic indicators of a poorer RFS rate in patients with EOC (hazard ratio, 2.265; 95% confidence interval, 1.072-8.021; P=0.0349). Confining analysis to patients with the clear-cell/mucinous histological type, those with moderate/strong ZEB1 expression demonstrated a significantly poorer RFS rate (P=0.0025). Positive ZEB1 expression may be an indicator to predict unfavorable RFS in patients with EOC.

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Section: Discussionmentioning

confidence: 99%

Impact of positive ZEB1 expression in patients with epithelial ovarian carcinoma as an oncologic outcome-predicting indicator

et al. 2017

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“…For example, at >0.95 precision, SCENIC finds 25 relevant TFs, while the next performing method detected only 10 relevant TFs at even lower precision (~0.85). Overall, SCENIC could potentially identify up to 212 out of 310 TFs detected at protein level in the mouse brain by Zhou et al (65 TFs would be missed because they are not detected in the scRNA-seq dataset, and only 38 because they have no motifs annotated in RcisTarget databases, Figure S6b).…”

Section: Comparison With Other Methodsmentioning

confidence: 99%

SCENIC: Single-cell regulatory network inference and clustering

Aibar

González-Blas

Moerman

et al. 2017

Preprint

886

1,482

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Single-cell RNA-seq allows building cell atlases of any given tissue and infer the dynamics of cellular state transitions during developmental or disease trajectories. Both the maintenance and transitions of cell states are encoded by regulatory programs in the genome sequence. However, this regulatory code has not yet been exploited to guide the identification of cellular states from single-cell RNA-seq data. Here we describe a computational resource, called SCENIC (Single Cell rEgulatory Network Inference and Clustering), for the simultaneous reconstruction of gene regulatory networks (GRNs) and the identification of stable cell states, using single-cell RNA-seq data. SCENIC outperforms existing approaches at the level of cell clustering and transcription factor identification. Importantly, we show that cell state identification based on GRNs is robust towards batch-effects and technical-biases. We applied SCENIC to a compendium of single-cell data from the mouse and human brain and demonstrate that the proper combinations of transcription factors, target genes, enhancers, and cell types can be identified. Moreover, we used SCENIC to map the cell state landscape in melanoma and identified a gene regulatory network underlying a proliferative melanoma state driven by MITF and STAT and a contrasting network controlling an invasive state governed by NFATC2 and NFIB. We further validated these predictions by showing that two transcription factors are predominantly expressed in early metastatic sentinel lymph nodes. In summary, SCENIC is the first method to analyze scRNA-seq data using a network-centric, rather than cell-centric approach. SCENIC is generic, easy to use, and flexible, and allows for the simultaneous tracing of genomic regulatory programs and the mapping of cellular identities emerging from these programs. Availability: SCENIC is available as an R workflow based on three new R/Bioconductor packages: GENIE3, RcisTarget and AUCell. As scalable alternative to GENIE3, we also provide GRNboost, paving the way towards the network analysis across millions of single cells.

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“…Human melanoma cells (400 cells) were seeded into 6-well plates and cultured in the presence of PLX4032 (5 mM) or DMSO as previously described (14), unless stated otherwise. Media were changed every 2-3 d. After 10-14 d of culture, the cells were fixed and stained with crystal violet.…”

Section: Clonogenesis Assaymentioning

confidence: 99%

Cell surface CD63 increased by up‐regulated polylactosamine modification sensitizes human melanoma cells to the BRAF inhibitor PLX4032

et al. 2018

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The BRAF inhibitor PLX4032 is effective in treating BRAF‐mutated melanoma; however, because drug resistance develops in most cases, it is critical to develop a new strategy for inhibiting drug‐resistant melanoma growth. The melanoma‐associated membrane glycoprotein CD63 is involved in cell proliferation and metastasis. Here, we found that cell surface CD63 suppresses the proliferation of human melanoma cells and PLX4032‐resistant cells. Endogenous CD63 protein levels were negatively correlated with PLX4032 resistance of human melanoma cell lines. CD63 overexpression in these cells, in which endogenous CD63 levels are low, suppressed cell proliferation under PLX4032 treatment. The cell surface levels and average molecular mass of CD63 were increased with PLX4032 treatment because of the up‐regulated polylactosamine modification caused by induced β1,3‐N‐acetylglucosami‐nyltransferase 2 expression, which is involved in polylactosamine synthesis. Forced cell surface localization of CD63 led to reduced melanoma cell proliferation without PLX4032 treatment. CD63 overexpression in PLX4032‐resistant cells, in which CD63 levels were lower and cell surface polylactosamine levels were higher than those in parental cells, effectively suppressed proliferation. Our study shows the potential of CD63 to sensitize melanoma cells to PLX4032 and to reduce the proliferation of PLX4032‐resistant cells.—Kudo, K., Yoneda, A., Sakiyama, D., Kojima, K., Miyaji, T., Yamazaki, M., Yaita, S., Hyodo, T., Satow, R., Fukami, K. Cell surface CD63 increased by up‐regulated polylactosamine modification sensitizes human melanoma cells to the BRAF inhibitor PLX4032. FASEB J. 33,3851–3869 (2019). http://www.fasebj.org

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ZEB 1‐mediated melanoma cell plasticity enhances resistance to MAPK inhibitors

Cited by 110 publications

References 57 publications

Impact of positive ZEB1 expression in patients with epithelial ovarian carcinoma as an oncologic outcome-predicting indicator

Impact of positive ZEB1 expression in patients with epithelial ovarian carcinoma as an oncologic outcome-predicting indicator

SCENIC: Single-cell regulatory network inference and clustering

Cell surface CD63 increased by up‐regulated polylactosamine modification sensitizes human melanoma cells to the BRAF inhibitor PLX4032

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