Targeting Dedifferentiated Melanoma: Exploring the Role of MECOM in Melanoma Phenotype Switching

Abstract

Despite major advances in immunotherapy and targeted treatments, resistance and disease progression remain significant challenges in advanced melanoma. Phenotype switching from a melanocytic to a dedifferentiated state underlies therapy resistance, yet the transcriptional regulators driving this plasticity remain poorly defined. MECOM, a zinc‑finger transcription factor and proto‑oncogene, is highly mutated in melanoma and implicated in lineage specification and oncogenic signalling in other cancers. This study investigated MECOM’s functional role in melanoma phenotype‑associated traits and its clinical relevance in the context of immune checkpoint therapy.

Using lentiviral models, MECOM expression was modulated in melanoma cell lines representing distinct differentiation states. MECOM overexpression in melanocytic cells enhanced proliferation, migration, and clonogenic survival, and modestly increased sensitivity to ferroptosis‑inducing drugs, whereas knockdown in dedifferentiated cells produced variable effects on growth and ferroptosis vulnerability. These findings indicate that MECOM acts as a permissive, context‑dependent modulator of aggressive traits rather than a dominant driver of phenotype switching.

Analysis of clinically annotated melanoma datasets showed that higher MECOM expression and MECOM missense mutations were associated with improved survival in anti–PD‑1–treated patients and correlated with an inflamed, interferon‑rich tumour microenvironment. Conversely, low MECOM expression was more frequently associated with brain metastases. Together, these findings position MECOM as a context‑dependent regulator of melanoma biology with potential relevance as a biomarker of immune responsiveness and therapeutic vulnerability.