ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions

作者：Simon Durand, Yaqi Tang, Roxane M. Pommier, Valentin Benboubker, Maxime Grimont, Félix Boivin, Laetitia Barbollat‐Boutrand, Eric Cumunel, Florian Dupeuble, Anaïs Eberhardt, Maud Plaschka, Stéphane Dalle, Julie Caramel · 发表于：Oncogene · 年份：2024 · DOI：10.1038/s41388-024-03010-7 · 被引用次数：25 · 研究领域：Single-cell and spatial transcriptomics、Cancer Cells and Metastasis、Gene Regulatory Network Analysis

Cell plasticity sustains intra-tumor heterogeneity and treatment resistance in melanoma. Deciphering the transcriptional mechanisms governing reversible phenotypic transitions between proliferative/differentiated and invasive/stem-like states is required. Expression of the ZEB1 transcription factor is frequently activated in melanoma, where it fosters adaptive resistance to targeted therapies. Here, we performed a genome-wide characterization of ZEB1 transcriptional targets, by combining ChIP-sequencing and RNA-sequencing, upon phenotype switching in melanoma models. We identified and validated ZEB1 binding peaks in the promoter of key lineage-specific genes crucial for melanoma cell identity. Mechanistically, ZEB1 negatively regulates SOX10-MITF dependent proliferative/melanocytic programs and positively regulates AP-1 driven invasive and stem-like programs. Comparative analyses with breast carcinoma cells revealed lineage-specific ZEB1 binding, leading to the design of a more reliable melanoma-specific ZEB1 regulon. We then developed single-cell spatial multiplexed analyses to characterize melanoma cell states intra-tumoral heterogeneity in human melanoma samples. Combined with scRNA-Seq analyses, our findings confirmed increased ZEB1 expression in Neural-Crest-like cells and mesenchymal cells, underscoring its significance in vivo in both populations. Overall, our results define ZEB1 as a major transcriptional regulator of cell states transitions and provide a better under...