Robust gene expression programs underlie recurrent cell states and phenotype switching in melanoma.

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.

• Authors: Jasper Wouters, Zeynep Kalender-Atak, Liesbeth Minnoye, Katina I Spanier, Maxime De Waegeneer, Carmen Bravo González-Blas, David Mauduit, Kristofer Davie, Gert Hulselmans, Ahmad Najem, Michael Dewaele, Dennis Pedri, Florian Rambow, Samira Makhzami, Valerie Christiaens, Frederik Ceyssens, Ghanem Ghanem, Jean-Christophe Marine, Suresh Poovathingal, Stein Aerts
• Journal: Nature cell biology (Nat Cell Biol) Vol. 22 Issue 8 Pg. 986-998 (08 2020) ISSN: 1476-4679 [Electronic] England
• PMID: 32753671 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Neoplasm
• SOX10 protein, human
• SOXE Transcription Factors
• Transcription Factors

Topics

• Cell Line, Tumor
• Cell Movement
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Humans
• Melanoma (genetics, pathology)
• Phenotype
• RNA, Neoplasm
• RNA-Seq
• SOXE Transcription Factors (metabolism)
• Transcription Factors (metabolism)
• Transcription, Genetic