Persister state-directed transitioning and vulnerability in melanoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA574414 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10191354.fastq.gz | Fastqsanger.gz | |||
| SRR10191355.fastq.gz | Fastqsanger.gz | |||
| SRR10191356.fastq.gz | Fastqsanger.gz | |||
| SRR10191357.fastq.gz | Fastqsanger.gz | |||
| SRR10191358.fastq.gz | Fastqsanger.gz |
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Project description:Persister state-directed transitioning and vulnerability in melanoma
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Project description:Melanoma is a highly plastic tumor characterized by dynamic interconversion of different cell identities depending on the biological context. For example, melanoma cells with high expression of the H3K4 demethylase KDM5B (JARID1B) rest in a slow-cycling, yet reversible persister state. Over time, KDM5Bhigh cells can promote rapid tumor repopulation with equilibrated KDM5B expression heterogeneity. The cellular identity of KDM5Bhigh persister cells has not been studied so far, missing an important cell state-directed treatment opportunity in melanoma. Here, we have established a doxycycline-titratable system for genetic induction of permanent intratumor expression of KDM5B and screened for chemical agents that phenocopy this effect. Transcriptional profiling and cell functional assays confirmed that the dihydropyridine phenoxyethyl 4-(2-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxylate (termed Cpd1) supports high KDM5B expression and directs melanoma cells towards differentiation along the melanocytic lineage and to cell cycle-arrest. The high KDM5B state additionally prevents cell proliferation through negative regulation of cytokinetic abscission. Moreover, treatment with Cpd1 promoted the expression of the melanocyte-specific tyrosinase gene specifically sensitizing melanoma cells for the tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG). In summary, our study provides proof-of-concept for a new dual hit strategy in melanoma, in which persister state-directed transitioning limits tumor growth and plasticity and primes melanoma cells towards lineage-specific elimination.
2022-03-14 | GSE168192 | GEO
Project description:Melanoma is a highly plastic tumor characterized by dynamic interconversion of different cell identities depending on the biological context. Melanoma cells with high expression of the H3K4 demethylase KDM5B (JARID1B) rest in a slow-cycling, yet reversible persister state. Over time, KDM5Bhigh cells can promote rapid tumor repopulation with equilibrated KDM5B expression heterogeneity. The cellular identity of KDM5Bhigh persister cells has not been studied so far, missing an important cell state-directed treatment opportunity in melanoma. Here, we have established a doxycycline-titratable system for genetic induction of permanent intratumor expression of KDM5B and screened for chemical agents that phenocopy this effect. Transcriptional profiling and cell functional assays confirmed that the dihydropyridine 2-phenoxyethyl 4-(2-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxylate (termed Cpd1) supports high KDM5B expression and directs melanoma cells towards differentiation along the melanocytic lineage and to cell cycle-arrest. The high KDM5B state additionally prevents cell proliferation through negative regulation of cytokinetic abscission. Moreover, treatment with Cpd1 promoted the expression of the melanocyte-specific tyrosinase gene specifically sensitizing melanoma cells for the tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG). In summary, our study provides proof-of-concept for a dual hit strategy in melanoma, in which persister state-directed transitioning limits tumor plasticity and primes melanoma cells towards lineage-specific elimination.
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Project description:Phenotypic heterogeneity and plasticity represent major drivers of tumor relapse in melanoma. Expression of the H3K4 demethylase and pRB-binding protein JARID1B/KDM5B follows a dynamic continuum across melanoma cells. Highly JARID1B-expressing cells are enriched after short-term drug treatment. However, under persistent drug-exposure, JARID1B heterogeneity is reconstituted. Using a doxycycline-titratable system and a novel chemical enhancer of JARID1B-expression, we found that JARID1Bhigh cells are transiently 'pseudo-differentiated'. Melanoma cells use this JARID1Bhigh growth-arrested state to survive drugs, but must decrease JARID1B expression again to re-enter cell cycling for long-term tumor repopulation. Overcoming the reversion to phenotypic heterogeneity by exogenous homogenization of the JARID1Bhigh phenotype causes tumor growth arrest, also in MAPKi-resistant melanoma. Mechanistically, JARID1B represents an integral checkpoint for coordinating cell differentiation via transcriptional control, stabilization of hypophosphorylated pRB, and attenuation of cytokinetic abscission. Thus, the plasticity among tumor differentiation states per se represents a novel therapeutic target, which can be chemically overcome.
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Project description:Cancer persister cells which survive oncogene targeted therapies are sensitized to ferroptosis but mechanistic understanding of this vulnerability remains limited. Here, we found that while levels of iron, glutathione and various ferroptosis suppressing enzymes vary among persister cell types, ferroptosis suppressor protein 1 (FSP1) is downregulated in multiple persister cell types and persister cells which survive glutathione peroxidase 4 (GPX4) inhibition rely upon residual FSP1 to survive. Furthermore, persister cells which survive GPX4 inhibition downregulate oxidative phosphorylation, a key source of mitochondrial reactive oxygen species which are required for persister cell ferroptosis. We also found that persister cell treatment with histone deacetylase inhibitors induce reactive oxygen species and sensitize multiple persister cell types to GPX4 inhibition. Together, these findings reveal that FSP1 and histone deacetylases suppress persister cell ferroptosis.
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Project description:Identify transcriptionnally and translationally regulated mRNA in melanoma parental and persister cells In this dataset, we include expression data of A375 melanoma drug-naïve parental cells and A375 melanoma persister cells that survived from BRAF and MEK inhibition. The expression data are studied in both total RNA and polysome-bounded RNA.
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Project description:We study the m6A distribution on mRNAs from melanoma drug-naïve parental and persister cells treated with BRAF and MEK inhibitors.
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