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Lentiviral hTERT overexpression extends the lifespan of primary human epidermal melanocytes and reshapes transcriptional programs

ABSTRACT: Lentiviral hTERT overexpression can generate expandable epidermal melanocyte models that preserve closer global similarity to primary melanocytes than melanoma cell lines. Nevertheless, hTERT overexpression and subsequent clonal selection induced broad remodeling of genes and pathways associated with cell-cycle progression, telomere regulation, antiviral immune response, extracellular matrix organization, cell adhesion, dendrite-associated structures, and pigmentation. These findings indicate that lentiviral hTERT overexpression extends the lifespan of human epidermal melanocytes but is not functionally neutral. Instead, this process promotes dedifferentiation and compromises key melanocytic functions. Moreover, single-cell cloning appears to impose additional selection pressure and may further drive model drift. hTERT-extended melanocytes should therefore be used cautiously in studies involving pigmentation, adhesion, differentiation, and normal melanocyte physiology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE338364 | GEO | 2026/07/24

REPOSITORIES: GEO

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Project description:Dysfunctions in melanocytes can lead to pigmentation disorders, such as albinism, or contribute to the development of melanoma, the most aggressive form of skin cancer. Epidermal melanocytes typically interact with the collagen IV-rich basement membrane, but upon injury or in pathological conditions, they can encounter environments rich in collagen I or fibronectin. While alterations in ECM composition and stiffness are known to impact cell behavior, the specific roles of each of these cues for melanocyte functions remain unclear. To explore the impact of these extrinsic cues, we here exposed murine melanocytes to different ECM proteins as well as varying substrate stiffnesses. This study identified MITF, a key regulator of melanocyte differentiation and function, as an ECM- and mechanosensitive transcription factor. We further revealed that distinct ECM proteins and substrate stiffness engage a FAK/MEK/ERK/MITF signaling axis to control melanocyte functions. Exposure of melanocytes to collagen I restricted FAK and ERK activation, promoting high nuclear MITF levels associated with melanocyte proliferation and differentiation. Conversely, fibronectin elicited elevated FAK and ERK activation, leading to low nuclear MITF, correlating with a dedifferentiated and motile phenotype. Consistent with these observations, RNA sequencing revealed that COL I supports a differentiated gene expression program, whereas FN induces a neural crest-like and dedifferentiated transcriptomic signature. Importantly, inhibiting MEK or ERK activity in melanocytes cultured on fibronectin led to increased MITF nuclear localization, and enhanced melanogenesis. Additionally, we uncovered that melanocyte mechanoresponses differ depending on the specific ECM environment. Together, these findings reveal a synergistic effect of extrinsic cues on melanocyte function, with a context-dependent MITF regulation downstream of ERK, offering new perspectives for our understanding of melanocyte-related pathologies.

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Lentiviral hTERT overexpression extends the lifespan of primary human epidermal melanocytes and reshapes transcriptional programs

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