Heterogeneity in Melanoma

Shannan, Batool; Perego, Michela; Somasundaram, Rajasekharan; Herlyn, Meenhard

doi:10.1007/978-3-319-22539-5_1

Cited by 66 publications

(49 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The data utilized in this study were derived from a cutaneous melanoma (20) patient (patient 10) with a BRAF V600E mutation (3). The patient presented with primary melanoma on the back and bilateral axillary nodal metastasis.…”

Section: Resultsmentioning

confidence: 99%

Next-Generation Sequencing Analysis and Algorithms for PDX and CDX Models

Khandelwal

Girotti

Smowton

et al. 2017

Molecular Cancer Research

View full text Add to dashboard Cite

Patient-derived xenograft (PDX) and circulating tumor cellderived explant (CDX) models are powerful methods for the study of human disease. In cancer research, these methods have been applied to multiple questions, including the study of metastatic progression, genetic evolution, and therapeutic drug responses. As PDX and CDX models can recapitulate the highly heterogeneous characteristics of a patient tumor, as well as their response to chemotherapy, there is considerable interest in combining them with next-generation sequencing to monitor the genomic, transcriptional, and epigenetic changes that accompany oncogenesis. When used for this purpose, their reliability is highly dependent on being able to accurately distinguish between sequencing reads that originate from the host, and those that arise from the xenograft itself. Here, we demonstrate that failure to correctly identify contaminating host reads when analyzing DNAand RNA-sequencing (DNA-Seq and RNA-Seq) data from PDX and CDX models is a major confounding factor that can lead to incorrect mutation calls and a failure to identify canonical mutation signatures associated with tumorigenicity. In addition, a highly sensitive algorithm and open source software tool for identifying and removing contaminating host sequences is described. Importantly, when applied to PDX and CDX models of melanoma, these data demonstrate its utility as a sensitive and selective tool for the correction of PDX-and CDX-derived wholeexome and RNA-Seq data.

show abstract

Section: Resultsmentioning

confidence: 99%

Next-Generation Sequencing Analysis and Algorithms for PDX and CDX Models

Khandelwal

Girotti

Smowton

et al. 2017

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…Given melanoma heterogeneity and melanoma cell plasticity, the identification of a unique marker able to select cells with CSC features has been challenging [59]. We have previously shown that ALDH high cells in melanoma retain a CSC phenotype and recently, a role for SOX2 in sustaining the tumorigenic ability of ALDH high melanoma cells has been demonstrated [49].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic potential of the metabolic modulator phenformin in targeting the stem cell compartment in melanoma

et al. 2016

View full text Add to dashboard Cite

Melanoma is the most dangerous and treatment-resistant skin cancer. Tumor resistance and recurrence are due to the persistence in the patient of aggressive cells with stem cell features, the cancer stem cells (CSC). Recent evidences have shown that CSC display a distinct metabolic profile as compared to tumor bulk population: a promising anti-tumor strategy is therefore to target specific metabolic pathways driving CSC behavior. Biguanides (metformin and phenformin) are anti-diabetic drugs able to perturb cellular metabolism and displaying anti-cancer activity. However, their ability to target the CSC compartment in melanoma is not known. Here we show that phenformin, but not metformin, strongly reduces melanoma cell viability, growth and invasion in both 2D and 3D (spheroids) models. While phenformin decreases melanoma CSC markers expression and the levels of the pro-survival factor MITF, MITF overexpression fails to prevent phenformin effects. Phenformin significantly reduces cell viability in melanoma by targeting both CSC (ALDHhigh) and non-CSC cells and by significantly reducing the number of viable cells in ALDHhigh and ALDHlow-derived spheroids. Consistently, phenformin reduces melanoma cell viability and growth independently from SOX2 levels. Our results show that phenformin is able to affect both CSC and non-CSC melanoma cell viability and growth and suggests its potential use as anti-cancer therapy in melanoma.

show abstract

“…Melanoma cells are very early phenotypically diversified and undergo phenotype switching resembling the EMT, through which they acquire considerable microheterogeneity resulting in plasticity, capability of invasion and migration. These properties lead to metastasis and poor prognosis [4][5][6][7]. EMT is mostly a reversible process through which undergoes epithelial tumours to gain the mesenchymal phenotype and more oncogenic characteristics but occurs also in non-epithelial cancers [8,9].…”

Section: Introductionmentioning

confidence: 99%

Inducibly decreased MITF levels do not affect proliferation and phenotype switching but reduce differentiation of melanoma cells

Vlčková

Vachtenheim

Réda

et al. 2018

J Cellular Molecular Medi

View full text Add to dashboard Cite

Melanoma arises from neural crest‐derived melanocytes which reside mostly in the skin in an adult organism. Epithelial–mesenchymal transition (EMT) is a tumorigenic programme through which cells acquire mesenchymal, more pro‐oncogenic phenotype. The reversible phenotype switching is an event still not completely understood in melanoma. The EMT features and increased invasiveness are associated with lower levels of the pivotal lineage identity maintaining and melanoma‐specific transcription factor MITF (microphthalmia‐associated transcription factor), whereas increased proliferation is linked to higher MITF levels. However, the precise role of MITF in phenotype switching is still loosely characterized. To exclude the changes occurring upstream of MITF during MITF regulation in vivo, we employed a model whereby MITF expression was inducibly regulated by shRNA in melanoma cell lines. We found that the decrease in MITF caused only moderate attenuation of proliferation of the whole cell line population. Proliferation was decreased in five of 15 isolated clones, in three of them profoundly. Reduction in MITF levels alone did not generally produce EMT‐like characteristics. The stem cell marker levels also did not change appreciably, only a sharp increase in SOX2 accompanied MITF down‐regulation. Oppositely, the downstream differentiation markers and the MITF transcriptional targets melastatin and tyrosinase were profoundly decreased, as well as the downstream target livin. Surprisingly, after the MITF decline, invasiveness was not appreciably affected, independently of proliferation. The results suggest that low levels of MITF may still maintain relatively high proliferation and might reflect, rather than cause, the EMT‐like changes occurring in melanoma.

show abstract

Heterogeneity in Melanoma

Cited by 66 publications

References 71 publications

Next-Generation Sequencing Analysis and Algorithms for PDX and CDX Models

Next-Generation Sequencing Analysis and Algorithms for PDX and CDX Models

Therapeutic potential of the metabolic modulator phenformin in targeting the stem cell compartment in melanoma

Inducibly decreased MITF levels do not affect proliferation and phenotype switching but reduce differentiation of melanoma cells

Contact Info

Product

Resources

About