A BRN2:MYC transcriptional axis regulates interconversion between therapy-resistant and tumorigenic phenotypes in melanoma

TL;DR

The study identifies two key transcriptional states in melanoma cells that influence tumor growth and resistance to treatment, revealing potential new targets for therapy.

Contribution

The discovery of a BRN2:MYC transcriptional axis that regulates phenotypic switching in melanoma, distinguishing it from melanocytes.

Findings

Melanoma cells switch between an MYC-driven tumor-initiating state and a BRN2-high therapy-resistant state.

Transitions between these states involve MITF-high intermediate states and occur more frequently in melanoma than in melanocytes.

The BRN2-high state is present in both melanoma and melanocytes, but the MYC state is unique to melanoma.

Abstract

Metastatic spread and therapeutic resistance are the principal causes of cancer mortality. For melanoma, these processes rely on the capacity of cells to switch between transcriptional states. Although targeting transcriptional states pharmacologically is promising, the mechanisms by which melanoma cells switch between states—and how these processes differ from melanocytes—remain poorly understood. Here, we isolate distinct melanoma states with unique phenotypes: a MYC-driven state, essential for tumor initiation yet sensitive to BRAF inhibition, and a dedifferentiated, invasive BRN2-high state enriched in therapy-resistant cells but not directly tumorigenic. Transitions between phenotypes occur through intermediate, more differentiated states. Unexpectedly, the BRN2-high state is also present in melanocytes, whereas the MYC state is exclusive to melanoma. Melanoma cells also exhibit an increased frequency of transitions across states. These findings highlight that accelerated phenotypic switching, rather than mere state diversity, is a defining feature of melanoma progression.

Zhang et al. identify transcriptional states in melanoma, defining an MYC-driven tumor-initiating state and a BRN2-high invasive, therapy-resistant state bridged by MITF-high intermediates. While melanocytes share most states, melanoma uniquely acquires the MYC state and transitions more frequently, revealing plasticity as a therapeutic vulnerability.

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