A Brn2:Myc Transcriptional Axis Regulates Interconversion Between Therapy-Resistant and Tumorigenic Phenotypes in Melanoma Publisher Pubmed



Zhang Y ; Urquijo MA ; Zitnay RG ; Marks K ; Belote RL ; Hansen MMK ; Ferita M ; Neuendorf HM ; Liu T ; Smith EA ; Mehrabad EM ; Hejna M ; Moustafa TE ; Lange D Show All Authors
Source: Cell Reports Published:2025

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. © 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/