Melanoma Progression Inhibits Pluripotency and Differentiation of Melanoma-Derived iPSCs Produces Cells with Neural-like Mixed Dysplastic Phenotype

Castro‐Pérez, Edgardo; Rodríguez, Carlos; Mikheil, Dareen M.; Siddique, Shakir; McCarthy, Alexandra; Newton, Michael A.; Setaluri, Vijayasaradhi

doi:10.1016/j.stemcr.2019.05.018

Cited by 14 publications

(37 citation statements)

References 40 publications

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“…Lentiviruses were prepared as described previously [ 48 ]. Briefly, HEK293 cells were plated on 10 cm plates in DMEM and 10% FBS without antibiotics and allowed to reach a 90% confluence within 24–48 h. Following the use of a Lipofectamine 2000 (Thermo Fisher, Waltham, MA, USA, #11668019), the protocol cells were then triple co-transfected with plasmids containing the packaging (psPAX2, Addgene #12260) and a VSV G envelope (pMD2.G, Addgene #12259, Watertown, MA, USA) as well as the target genes BRAF V600E -GFP (a gift from Dr. Raabe [ 49 ]) or empty vector-GFP (a gift from Dr. Herlyn [ 50 ]).…”

Section: Methodsmentioning

confidence: 99%

Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes

Sadangi

Milosavljevic

Castro‐Pérez

et al. 2022

Cancers

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BRAFV600E is the most common mutation driver in melanoma. This mutation is known to cause a brief burst of proliferation followed by growth arrest and senescence, which prevent an uncontrolled cell proliferation. This phenomenon is known as oncogene-induced senescence (OIS) and OIS escape is thought to lead to melanomagenesis. Much attention has been focused on the melanocyte-intrinsic mechanisms that contribute to senescence escape. Additional genetic events such as the loss of tumor suppressor PTEN and/or epigenetic changes that contribute to senescence escape have been described. However, the role of the skin microenvironment—specifically, the role of epidermal keratinocytes—on melanomagenesis is not fully understood. In this study, we employ a microfluidic platform to study the interaction between melanocytes expressing the BRAFV600E mutation as well as keratinocytes and dermal fibroblasts. We demonstrate that keratinocytes suppress senescence-related genes and promote the proliferation of transformed melanocytes. We also show that a keratinocyte-conditioned medium can alter the secretion of both pro- and anti-tumorigenic factors by transformed melanocytes. In addition, we show that melanocytes and keratinocytes from donors of white European and black African ancestry display different crosstalks; i.e., white keratinocytes appear to promote a more pro-tumorigenic phenotype compared with black keratinocytes. These data suggest that keratinocytes exert their influence on melanomagenesis both by suppressing senescence-related genes in melanocytes and by affecting the balance of the melanocyte-secreted factors that favor tumorigenesis.

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Section: Methodsmentioning

confidence: 99%

Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes

Sadangi

Milosavljevic

Castro‐Pérez

et al. 2022

Cancers

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“…In a previous study aimed at understanding the relationship between melanoma plasticity and MAPKi resistance, we performed whole transcriptome sequence (RNAseq) analysis of MAPKi-sensitive and MAPKi-resistant (both intrinsic and acquired) melanoma cell lines [14].…”

Section: Gene Expression Signatures Of Drug Resistant Melanoma Cellsmentioning

confidence: 99%

“…Recently, using a strategy of reprogramming human melanoma cells to induced-pluripotent cell (iPSC)-like state, we showed that melanoma-derived iPSC-like cells tend to differentiate along mixed-melanocytic and neural-cell lineages, both in vitro and in vivo. These differentiated/transdifferentiated cells also exhibit MAPKi resistance [14] suggesting a relationship between signaling pathways that control transdifferentiation and MAPKi-resistance. This notion is supported by the observation that transdifferentiation to neuroendocrine phenotype correlates with treatment resistance in prostate and lung cancers [5,[15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Dual Specificity Phosphatase 1 (DUSP1) Provides Mechanistic Link Between Melanoma Cellular Plasticity and Drug Resistance

Setaluri

Singh

Altameemi

et al. 2022

Preprint

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Melanoma cells exhibit phenotypic plasticity that allows transition from a proliferative and differentiated phenotype to a more invasive and undifferentiated or transdifferentiated phenotype often also associated with drug resistance. The mechanisms involved in melanoma phenotype plasticity and its role in drug resistance are not fully understood. We previously demonstrated that the MAPK inhibitors (MAPKi)-resistance phenotype is associated with decreased expression of stem cell proliferation genes and increased expression of MAPK inactivation genes, including dual specificity phosphatases (DUSPs). Several members of the DUSP family genes, specifically DUSP1, -3, -8 and -9, are expressed in primary and metastatic melanoma cell lines and pre-and post BRAFi treated patient tumor cells. Here, we show that was knockdown of DUSP1 or DUSP8 or treatment with BCI, a pharmacological inhibitor of DUSP1/6 decreases the survival of MAPKi-resistant cells and sensitizes them to MAPKi. We also show that nestin, a neural crest stem cell marker, and MAP2, a neuronal differentiation marker, are downregulated in MAPKi-resistant cells whereas GFAP, a glial cell marker, present in both MAPKi-sensitive and -resistant cells. Inhibition of DUSP1/6 upregulated nestin expression in MAPKi-sensitive cells and cells with acquired resistance. In contrast, treatment with BCI caused upregulation of MAP2 in MAPKi-sensitive cells and downregulation of both MAP2 and GFAP in all MAPKi-resistant cell lines. These data suggest that DUSP1/6 are involved in melanoma neuronal transdifferentiation serve as mechanistic link between melanoma drug resistance and melanoma differentiation and targets for treatment of MAPKi-resistant melanoma.

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“…In the case of hiPSCs, they retain the genetic background of the donor [ 363 ]. Both hiPSCs and hESCs have allowed the study of human cells which are not normally accessible to study in the human body (for example, neurons and glial cells of the human CNS) and, therefore, have boosted the possibilities in medical research employing human cell lines, permitting the study of mechanisms of human development [ 363 , 364 ]; in vitro disease modelling, including in cancer research [ 365 , 366 , 367 ]; in the development of assays and platforms for drug screening campaigns [ 355 , 368 , 369 ]; in patient stratification and in the development of cell replacement strategies [ 355 , 363 ]. The pioneer monolayer cultures gave way to organoids, spheroids, organ-on-a-chip approaches and more recently assembloids, which employ single cell types or a multitude of different cellular types [ 355 , 360 , 370 , 371 , 372 , 373 ].…”

Section: Current Challenges and Future Perspectives In Uveal Melanomamentioning

confidence: 99%

Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions

Lamas

Martel

Nahon-Estève

et al. 2021

Cancers

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Uveal melanoma (UM) is the most common malignant intraocular tumour in the adult population. It is a rare cancer with an incidence of nearly five cases per million inhabitants per year, which develops from the uncontrolled proliferation of melanocytes in the choroid (≈90%), ciliary body (≈6%) or iris (≈4%). Patients initially present either with symptoms like blurred vision or photopsia, or without symptoms, with the tumour being detected in routine eye exams. Over the course of the disease, metastases, which are initially dormant, develop in nearly 50% of patients, preferentially in the liver. Despite decades of intensive research, the only approach proven to mildly control disease spread are early treatments directed to ablate liver metastases, such as surgical excision or chemoembolization. However, most patients have a limited life expectancy once metastases are detected, since there are limited therapeutic approaches for the metastatic disease, including immunotherapy, which unlike in cutaneous melanoma, has been mostly ineffective for UM patients. Therefore, in order to offer the best care possible to these patients, there is an urgent need to find robust models that can accurately predict the prognosis of UM, as well as therapeutic strategies that effectively block and/or limit the spread of the metastatic disease. Here, we initially summarized the current knowledge about UM by compiling the most relevant epidemiological, clinical, pathological and molecular data. Then, we revisited the most important prognostic factors currently used for the evaluation and follow-up of primary UM cases. Afterwards, we addressed emerging prognostic biomarkers in UM, by comprehensively reviewing gene signatures, immunohistochemistry-based markers and proteomic markers resulting from research studies conducted over the past three years. Finally, we discussed the current hurdles in the field and anticipated the future challenges and novel avenues of research in UM.

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Melanoma Progression Inhibits Pluripotency and Differentiation of Melanoma-Derived iPSCs Produces Cells with Neural-like Mixed Dysplastic Phenotype

Cited by 14 publications

References 40 publications

Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes

Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes

Dual Specificity Phosphatase 1 (DUSP1) Provides Mechanistic Link Between Melanoma Cellular Plasticity and Drug Resistance

Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions

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