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

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

PROVIDER: PRJNA1034106 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26623057_1.fastq.gz	Fastqsanger.gz
	SRR26623057_2.fastq.gz	Fastqsanger.gz
	SRR26623058_1.fastq.gz	Fastqsanger.gz
	SRR26623058_2.fastq.gz	Fastqsanger.gz
	SRR26623059_1.fastq.gz	Fastqsanger.gz

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ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions [ChIP-seq]

Project description: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.

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ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions [RNA-seq]

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ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions [RNA-seq]

Project description:ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions [RNA-seq]

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ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions [ChIP-seq]

Project description:ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions [ChIP-seq]

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-03-25 | GSE246673 | GEO

ZEB1 insufficiency causes corneal endothelial cell state transition and altered cellular processing

Project description:The zinc finger e-box binding homeobox 1 (ZEB1) transcription factor is a master regulator of the epithelial to mesenchymal transition (EMT), and of the reverse mesenchymal to epithelial transition (MET) processes. ZEB1 plays an integral role in mediating cell state transitions during cell lineage specification, wound healing and disease. EMT/MET are characterized by distinct changes in molecular and cellular phenotype that are generally context-independent. Posterior polymorphous corneal dystrophy (PPCD), associated with ZEB1 insufficiency, provides a new biological context in which to understand and evaluate the classic EMT/MET paradigm. PPCD is characterized by a cadherin-switch and transition to an epithelial-like transcriptomic and cellular phenotype, which we study in a cell-based model of PPCD generated using CRISPR-Cas9-mediated ZEB1 knockout in corneal endothelial cells (CEnCs). Transcriptomic and functional studies support the hypothesis that CEnC undergo an MET-like transition in PPCD, termed endothelial to epithelial transition (EnET), and lead to the conclusion that EnET may be considered a corollary to the classic EMT/MET paradigm.

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TGFβ1 promotes collective invasion of oncogenically transformed intestinal organoids by inducing partial epithelial-mesenchymal transition independently of Snail1 and Zeb1

Project description:Cancer cells simultaneously featuring epithelial and mesenchymal traits appear particularly competent to invade and metastasize. However, genetic prerequisites and signaling pathways promoting such partial epithelial-to-mesenchymal transitions (EMT) remain obscure. Here we report that murine intestinal organoids with hyperactive Wnt and MAPK signaling, and mutant Trp53 are purely epithelial and non-invasive in vitro, but initiate a collective invasion program when treated with TGFβ1. Invasive organoids reciprocally interact with the extracellular matrix (ECM), and autonomously deposit and remodel components thereof. Although cells at the organoid/ECM interface shed certain epithelial characteristics, invasive organoids largely maintain epithelial gene expression while concomitantly upregulating a mesenchymal program. TGFβ1-induced phenotypic changes involve canonical, Smad4-dependent signaling, yet, are unimpeded by knockout of Snai1 and Zeb1 - otherwise key regulators of epithelial-to-mesenchymal transitions. The finding of TGFβ1-inducible, Snail1/Zeb1-independent collective invasion of oncogenically transformed intestinal organoids provides novel mechanistic insights and broadens the spectrum of context-dependent manifestations of partial EMT.

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Project description:The efficacy of immunotherapies in metastatic melanoma depends on a robust T cell infiltration. Consistently, defining cancer cell intrinsic mechanisms mediating T cell exclusion and immune resistance is crucial. The EMT inducing transcription factor ZEB1 is a major regulator of melanoma cell plasticity, driving resistance to MAPK targeted therapies. Here, by analyzing the immune infiltrates of a cohort of melanoma patients, we demonstrate that high ZEB1 expression in tumor cells is associated with a decrease in CD8+ T lymphocyte infiltration, independently of beta-catenin pathway activation. Moreover, gain- or loss-of-function experiments in melanoma mouse models show that ZEB1 regulates tumor growth by controlling CD8+ T cell recruitment, via its negative action on the production of T cell attracting chemokines, and that its targeting improves the efficacy of anti-PD1 immunotherapy. Overall, the major role of ZEB1 in preventing T cell infiltration suggests it may constitute a new target in metastatic melanoma.

2022-03-23 | GSE169203 | GEO

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Zeb1-induced metabolic reprogramming of glycolysis is essential for macrophage polarization in breast cancer

Project description:Aerobic glycolysis (the Warburg effect) has been demonstrated to facilitate tumor progression by producing lactate, which has important roles as a proinflammatory and immunosuppressive mediator. However, how aerobic glycolysis is directly regulated is largely unknown. Here, we show that ectopic Zeb1 directly increases the transcriptional expression of HK2, PFKP and PKM2, which are glycolytic rate-determining enzymes, thus promoting the Warburg effect and breast cancer proliferation, migration, and chemoresistance in vitro and in vivo. In addition, Zeb1 exerts its biological effects to induce glycolytic activity in response to hypoxia via the PI3K/Akt/HIF-1α signaling axis, which contributes to fostering an immunosuppressive tumor microenvironment (TME). Mechanistically, breast cancer cells with ectopic Zeb1 expression produce lactate in the acidic tumor milieu to induce the alternatively activated macrophage M2-like phenotype through stimulation of the PKA/CREB signaling pathway. Clinically, the expression of Zeb1 is positively correlated with dysregulation of aerobic glycolysis, accumulation of M2-like tumor-associated macrophages (TAMs) and a poor prognosis in patients with breast cancer. In conclusion, these findings identify a Zeb1-dependent mechanism as a driver of breast cancer progression that acts by stimulating tumor-macrophage interplay, which could be a viable therapeutic target for the treatment of advanced human cancers.

2022-03-09 | GSE189779 | GEO

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