1. Robust gene expression programs underlie recurrent cell states and phenotype switching in melanoma
- Author
-
David Mauduit, Maxime de Waegeneer, Florian Rambow, Dennis Pedri, Jean-Christophe Marine, Samira Makhzami, Carmen Bravo González-Blas, Zeynep Kalender-Atak, Kristofer Davie, Stein Aerts, Ghanem Elias Ghanem, Ahmad Najem, Suresh Poovathingal, Michael Dewaele, Valerie Christiaens, Liesbeth Minnoye, Jasper Wouters, Gert Hulselmans, Frederik Ceyssens, and Katina I. Spanier
- Subjects
Transcription, Genetic ,MIGRATION ,INVASION ,SOX10 ,Gene regulatory network ,Computational biology ,Biology ,ACTIVATION ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Cell Line, Tumor ,Gene expression ,Humans ,Gene Regulatory Networks ,RNA, Neoplasm ,RNA-Seq ,TRANSCRIPTION FACTOR ,Melanoma ,Transcription factor ,SIGNATURES ,030304 developmental biology ,0303 health sciences ,Gene knockdown ,Science & Technology ,IDENTIFICATION ,SOXE Transcription Factors ,REPRESSOR ,PROFILES ,Cell Biology ,Phenotype ,Chromatin ,Cell biology ,Gene Expression Regulation, Neoplastic ,DIFFERENTIATION ,030220 oncology & carcinogenesis ,Life Sciences & Biomedicine ,STEM-CELLS ,Transcription Factors - Abstract
Melanoma cells can switch between a melanocytic and a mesenchymal-like state. Scattered evidence indicates that additional intermediate state(s) may exist. Here, to search for such states and decipher their underlying gene regulatory network (GRN), we studied 10 melanoma cultures using single-cell RNA sequencing (RNA-seq) as well as 26 additional cultures using bulk RNA-seq. Although each culture exhibited a unique transcriptome, we identified shared GRNs that underlie the extreme melanocytic and mesenchymal states and the intermediate state. This intermediate state is corroborated by a distinct chromatin landscape and is governed by the transcription factors SOX6, NFATC2, EGR3, ELF1 and ETV4. Single-cell migration assays confirmed the intermediate migratory phenotype of this state. Using time-series sampling of single cells after knockdown of SOX10, we unravelled the sequential and recurrent arrangement of GRNs during phenotype switching. Taken together, these analyses indicate that an intermediate state exists and is driven by a distinct and stable 'mixed' GRN rather than being a symbiotic heterogeneous mix of cells. ispartof: NATURE CELL BIOLOGY vol:22 issue:8 pages:986-+ ispartof: location:England status: published
- Published
- 2020