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

TANG, Y.; Durand, S.; Pommier, R. M.; Benboubker, V.; Grimont, M.; Cumunel, E.; Boivin, F.; Dupeuble, F.; Barbollat, L.; Eberhardt, A.; Plaschka, M.; Dalle, S.; CARAMEL, J.

doi:10.1101/2023.02.10.526467

bioRxiv · 10.1101/2023.02.10.526467

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

TANG, Y.·Durand, S.·Pommier, R. M.·Benboubker, V.·Grimont, M.·Cumunel, E.·Boivin, F.·Dupeuble, F.·Barbollat, L.·Eberhardt, A.·Plaschka, M.·Dalle, S.·CARAMEL, J.

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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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/526467v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@6c487eorg.highwire.dtl.DTLVardef@10b52aborg.highwire.dtl.DTLVardef@60821eorg.highwire.dtl.DTLVardef@1fe9f90_HPS_FORMAT_FIGEXP M_FIG C_FIG

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TANG, Y., Durand, S., Pommier, R. M., Benboubker, V., Grimont, M., Cumunel, E., Boivin, F., Dupeuble, F., Barbollat, L., Eberhardt, A., Plaschka, M., Dalle, S., CARAMEL, J.. 2023-02-10. ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions. https://doi.org/10.1101/2023.02.10.526467

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