The ISR activation confers vulnerability to mitoribosome-targeting antibiotics in melanoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE177075 | GEO | 2021/07/15
REPOSITORIES: GEO
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Project description:The ISR activation confers vulnerability to mitoribosome-targeting antibiotics in melanoma
| PRJNA737120 | ENA
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Project description:Our aim is to compare whole-genome expression profiles of partially reprogrammed C790 melanoma murine cells ( - dox vs + dox) after treatment with trametinib, in order to identify potential candidates related with drug resistance.
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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.
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Project description:Melanoma exhibits numerous transcriptional cell states including neural crest-like cells as well as pigmented melanocytic cells. How these different cell states relate to distinct tumorigenic phenotypes remains unclear. Here, we use a zebrafish melanoma model to identify a transcriptional program linking the melanocytic cell state to a dependence on lipid droplets, the specialized organelle responsible for lipid storage. Single-cell RNA-sequencing of these tumors show a concordance between genes regulating pigmentation and those involved in lipid and oxidative metabolism. This state is conserved across human melanoma cell lines and patient tumors. This melanocytic state demonstrates increased fatty acid uptake, an increased number of lipid droplets, and dependence upon fatty acid oxidative metabolism. Genetic and pharmacologic suppression of lipid droplet production is sufficient to disrupt cell cycle progression and slow melanoma growth in vivo. Because the melanocytic cell state is linked to poor outcomes in patients, these data indicate a metabolic vulnerability in melanoma that depends on the lipid droplet organelle.
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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: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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2008-12-23 | E-GEOD-8164 | biostudies-arrayexpress