Phenotypic plasticity of melanocytes derived from human adult skin

Vidács, Dániel László; Veréb, Zoltán; Bozó, Renáta; Flink, Lili Borbála; Polyánka, Hilda; Németh, István; Póliska, Szilárd; Papp, Benjamin Tamás; Manczinger, Máté; Gáspár, Róbert; Mirdamadi, Mohsen; Kemény, Lajos; Bata‐Csörgő, Zsuzsanna

doi:10.1111/pcmr.13012

Cited by 11 publications

(16 citation statements)

References 70 publications

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“…Corroborating this observation, melanocytes grown in TPA-free media expressed higher levels of AXL ( Figure 4G–H ), lower levels of MLANA, a melanocyte differentiation marker, and presented greater activity of aldehyde dehydrogenase, enzymatic activity associated with stemness ( Figure 4I ). These results indicate that exposure to TPA induces a more differentiated melanocyte phenotype, consistent with previous reports ( Prince et al, 2003 ; Vidács et al, 2021 ; Kormos et al, 2011 ).…”

Section: Resultssupporting

confidence: 93%

BRAFV600E induces reversible mitotic arrest in human melanocytes via microRNA-mediated suppression of AURKB

McNeal

Belote

Zeng

et al. 2021

eLife

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Benign melanocytic nevi frequently emerge when an acquired BRAFV600E mutation triggers unchecked proliferation and subsequent arrest in melanocytes. Recent observations have challenged the role of oncogene-induced senescence in melanocytic nevus formation, necessitating investigations into alternative mechanisms for the establishment and maintenance of proliferation arrest in nevi. We compared the transcriptomes of melanocytes from healthy human skin, nevi, and melanomas arising from nevi and identified a set of microRNAs as highly expressed nevus-enriched transcripts. Two of these microRNAs—MIR211-5p and MIR328-3p—induced mitotic failure, genome duplication, and proliferation arrest in human melanocytes through convergent targeting of AURKB. We demonstrate that BRAFV600E induces a similar proliferation arrest in primary human melanocytes that is both reversible and conditional. Specifically, BRAFV600E expression stimulates either arrest or proliferation depending on the differentiation state of the melanocyte. We report genome duplication in human melanocytic nevi, reciprocal expression of AURKB and microRNAs in nevi and melanomas, and rescue of arrested human nevus cells with AURKB expression. Taken together, our data describe an alternative molecular mechanism for melanocytic nevus formation that is congruent with both experimental and clinical observations.

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Section: Resultssupporting

confidence: 93%

BRAFV600E induces reversible mitotic arrest in human melanocytes via microRNA-mediated suppression of AURKB

McNeal

Belote

Zeng

et al. 2021

eLife

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“…Although our study focuses on melanoma, EMT-like phenotypic switching is also characteristic of other non-epithelial cancers and de-differentiation of melanocytes independent of malignant transformation. De-differentiation of melanocytes into pluripotent stem cells demonstrated a reduction in expression levels of E-Cadherin, an epithelial marker, and similarities to mesenchymal stem cells ( 83 ). Molecular subtypes of glioblastoma multiforme (GBM), a non-epithelial cancer, include the pro-neural, classical, and mesenchymal phenotypes, which exist along a spectrum of worsening prognosis ( 84 ).…”

Section: Discussionmentioning

confidence: 99%

Mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis

et al. 2022

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Epithelial to mesenchymal transition (EMT) is a well-studied hallmark of epithelial-like cancers that is characterized by loss of epithelial markers and gain of mesenchymal markers. Melanoma, which is derived from melanocytes of the skin, also undergo phenotypic plasticity toward mesenchymal-like phenotypes under the influence of various micro-environmental cues. Our study connects EMT to the phenomenon of de-differentiation (i.e., transition from proliferative to more invasive phenotypes) observed in melanoma cells during drug treatment. By analyzing 78 publicly available transcriptomic melanoma datasets, we found that de-differentiation in melanoma is accompanied by upregulation of mesenchymal genes, but not necessarily a concomitant loss of an epithelial program, suggesting a more “one-dimensional” EMT that leads to a hybrid epithelial/mesenchymal phenotype. Samples lying in the hybrid epithelial/mesenchymal phenotype also correspond to the intermediate phenotypes in melanoma along the proliferative-invasive axis - neural crest and transitory ones. As melanoma cells progress along the invasive axis, the mesenchymal signature does not increase monotonically. Instead, we observe a peak in mesenchymal scores followed by a decline, as cells further de-differentiate. This biphasic response recapitulates the dynamics of melanocyte development, suggesting close interactions among genes controlling differentiation and mesenchymal programs in melanocytes. Similar trends were noted for metabolic changes often associated with EMT in carcinomas in which progression along mesenchymal axis correlates with the downregulation of oxidative phosphorylation, while largely maintaining glycolytic capacity. Overall, these results provide an explanation for how EMT and de-differentiation axes overlap with respect to their transcriptional and metabolic programs in melanoma.

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“…Within the EMU, the keratinocyte partner tightly controls several aspects of melanocyte behavior, including via a regulated balance of paracrine growth factors and cell-cell adhesion molecules. Distinct subpopulations of melanocytes seem to be differentially positioned within the basal layer of the human epidermis, generating at least two EMUs ( 28 , 29 ) (see below).…”

Section: Epidermal and Follicular Melanin Units Of Normal Skinmentioning

confidence: 99%

“…At least two subpopulations of melanocytes can be detected in the human epidermis, represented by different levels of differentiation, dendricity, activity of melanogenesis-related apparatus, and cell receptor expression ( 28 , 29 ). These melanocyte subpopulations appear to occupy different anatomical locations within the epidermis, with c-KIT + | CD90 + melanocytes more commonly distributed around the base of rete ridges ( 40 ) and more differentiated and dendritic melanocytes located more superficially, including in the inter-rete ridge epidermis ( Figure 2 ).…”

Section: Epidermal and Follicular Melanin Units Of Normal Skinmentioning

confidence: 99%

“…A hallmark of the comparative biology of epidermal and hair follicle melanocytes is the observation that melanogenesis in the latter is stringently coupled to the hair growth cycle (anagen-specific melanogenesis), while melanogenesis in the former is continuous, albeit often augmentable (e.g., after exposure to UVR). Up to 90% of melanomas are said to be ‘caused’ by UVR from sunlight ( 85 ), and while much incident UVB and UVA readily reaches melanocytes in the superficial epidermis, hair follicle melanocytes are located more deeply in the skin, most located well below the level of UVB penetration ( 18 , 29 ). That said, more superficially distributed melanocytes, e.g., in the upper infundibulum (In-FMU) and potentially also the bulge stem niche Stem-FMU), may receive carcinogenic doses of UVB.…”

Section: Emu Disruption During Primary Melanomagenesismentioning

confidence: 99%

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Loss of ‘Epidermal Melanin Unit’ Integrity in Human Skin During Melanoma-Genesis

et al. 2022

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Cutaneous melanoma can be a most challenging neoplasm of high lethality, in part due to its extreme heterogeneity and characteristic aggressive and invasive nature. Indeed, its moniker ‘the great masquerader’ reflects that not all melanomas are created equal in terms of their originating cellular contexts, but also that melanoma cells in the malignant tumor can adopt a wide range of different cell states and variable organotropism. In this review, we focus on the early phases of melanomagenesis by discussing how the originating pigment cell of the melanocyte lineage can be influenced to embark on a wide range of tumor fates with distinctive microanatomical pathways. In particular, we assess how cells of the melanocyte lineage can differ by maturation status (stem cell; melanoblast; transiently amplifying cell; differentiated; post-mitotic; terminally-differentiated) as well as by micro-environmental niche (in the stratum basale of the epidermis; within skin appendages like hair follicle, eccrine gland, etc). We discuss how the above variable contexts may influence the susceptibility of the epidermal-melanin unit (EMU) to become unstable, which may presage cutaneous melanoma development. We also assess how unique features of follicular-melanin unit(s) (FMUs) can, by contrast, protect melanocytes from melanomagenesis. Lastly, we postulate how variable melanocyte fates in vitiligo, albinism, psoriasis, and alopecia areata may provide new insights into immune-/non immune-mediated outcomes for melanocytes in cutaneous melanin units.

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Phenotypic plasticity of melanocytes derived from human adult skin

Cited by 11 publications

References 70 publications

BRAFV600E induces reversible mitotic arrest in human melanocytes via microRNA-mediated suppression of AURKB

BRAFV600E induces reversible mitotic arrest in human melanocytes via microRNA-mediated suppression of AURKB

Mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis

Loss of ‘Epidermal Melanin Unit’ Integrity in Human Skin During Melanoma-Genesis

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