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Phone: (843) 722-7550
West Ashley Library
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Phone: (843) 766-6635
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Phone: (843) 588-2001
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ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions
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- Author(s): Durand, Simon; Tang, Yaqi; Pommier, Roxane M.; Benboubker, Valentin; Grimont, Maxime; Boivin, Felix; Barbollat-Boutrand, Laetitia; Cumunel, Eric; Dupeuble, Florian; Eberhardt, Anaïs; Plaschka, Maud; Dalle, Stéphane; Caramel, Julie
- Source:
Oncogene; 20240101, Issue: Preprints p1-17, 17p - Source:
- Additional Information
- Abstract: 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 understanding of lineage-specific transcriptional programs sustaining intra-tumor heterogeneity in melanoma.
- Abstract:
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