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Immunometabolic actions of trabectedin and lurbinectedin on human macrophages: Relevance for their antitumor activity

ABSTRACT: Immunometabolic actions of trabectedin and lurbinectedin on human macrophages: Relevance for their antitumor activity

PROVIDER: PRJNA985776 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24974002_1.fastq.gz	Fastqsanger.gz
	SRR24974002_2.fastq.gz	Fastqsanger.gz
	SRR24974003_1.fastq.gz	Fastqsanger.gz
	SRR24974003_2.fastq.gz	Fastqsanger.gz
	SRR24974004_1.fastq.gz	Fastqsanger.gz

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Immunometabolic actions of trabectedin and lurbinectedin on human macrophages: Relevance for their antitumor activity

Project description:In recent years, it has been recognized the central role of cell bioenergetics in regulating immune cell function and fate giving rise to the interest in immunometabolism, an area of research focused on the interaction between metabolic regulation and immune function. Immunometabolism has been studied in the modulation of macrophage polarization. Thus, early metabolic changes associated with the polarisation of macrophages into pro-inflammatory or pro-resolving cells under different stimuli have been characterized. Tumour-associated macrophages are among the most abundant cells in the tumour microenvironment; however, it exists an unmet need to study the effect of chemotherapeutics on macrophage immunometabolism. Here, a systems biology approach that integrates transcriptomics and metabolomics unveils the immunometabolic effects of trabectedin (TRB) and lurbinectedin (LUR), two intercalating DNA agents with proved antitumor activity in the low nanomolar range. Our results show that TRB and LUR activate human macrophages towards a pro-inflammatory functional phenotype by inducing a specific metabolic rewiring program that includes ROS production and changes in the mitochondrial inner membrane potential, increased pentose phosphate pathway, TCA cycle serine and methylglyoxal pathways in human macrophages. glutamine, aspartate, histidine, and proline consumption are increased whereas 50 nM TRB increases lactate release and oxygen consumption is depressed . The observed immunometabolic rewiring could explain additional antitumor activities of these compounds and open new avenues to design therapeutic interventions that specifically target the immunometabolic landscape in the treatment of cancer.

2023-06-25 | GSE235390 | GEO

Immunometabolic actions of trabectedin and lurbinectedin on human macrophages: relevance for their anti-tumor activity.

Project description:In recent years, the central role of cell bioenergetics in regulating immune cell function and fate has been recognized, giving rise to the interest in immunometabolism, an area of research focused on the interaction between metabolic regulation and immune function. Thus, early metabolic changes associated with the polarization of macrophages into pro-inflammatory or pro-resolving cells under different stimuli have been characterized. Tumor-associated macrophages are among the most abundant cells in the tumor microenvironment; however, it exists an unmet need to study the effect of chemotherapeutics on macrophage immunometabolism. Here, we use a systems biology approach that integrates transcriptomics and metabolomics to unveil the immunometabolic effects of trabectedin (TRB) and lurbinectedin (LUR), two DNA-binding agents with proven antitumor activity. Our results show that TRB and LUR activate human macrophages toward a pro-inflammatory phenotype by inducing a specific metabolic rewiring program that includes ROS production, changes in the mitochondrial inner membrane potential, increased pentose phosphate pathway, lactate release, tricarboxylic acids (TCA) cycle, serine and methylglyoxal pathways in human macrophages. Glutamine, aspartate, histidine, and proline intracellular levels are also decreased, whereas oxygen consumption is reduced. The observed immunometabolic changes explain additional antitumor activities of these compounds and open new avenues to design therapeutic interventions that specifically target the immunometabolic landscape in the treatment of cancer.

| S-EPMC10479946 | biostudies-literature

Trabectedin Promotes Oncolytic Virus Antitumor Efficacy, Viral Gene Expression, and Immune Effector Function in Models of Bone Sarcoma

Project description:We previously reported that the DNA alkylator and transcriptional-blocking chemotherapeutic agent trabectedin enhances oncolytic herpes simplex viroimmunotherapy in human sarcoma xenograft models, though the mechanism remained to be elucidated. Here we report trabectedin disrupts the intrinsic cellular antiviral response which increases viral transcript presence in the human tumor cells. We also extended our synergy findings to syngeneic murine sarcoma models, which are poorly susceptible to virus infection. In the absence of robust virus replication, we found trabectedin enhanced viroimmunotherapy efficacy by reducing infiltrating immunosuppressive CD4 T and myeloid cells and stimulating granzyme expression in infiltrating T and natural killer cells to cause immune-mediated tumor regressions. Thus, trabectedin enhances both the direct virus-mediated killing of tumor cells and the viral-induced activation of cytotoxic effector lymphocytes to cause tumor regressions across models. Our data provide a strong rationale for clinical translation as both mechanisms should be simultaneously active in human patients.

2024-10-11 | GSE260551 | GEO

PARP1 expression drives the synergy between trabectedin and PARP1 inhibitors

Project description:Trabectedin is a DNA-damaging agent with a peculiar mechanism of action; it traps the DNA repair machinery leading to DNA single- and double-strand breaks, particularly in BRCA1/2-deficient tumors. We hypothesized that trabectedin-induced DNA damage might activate PARP1 (a DNA-repair machinery key player), and consequently, PARP1 inhibition would perpetuate trabectedin-induced DNA damage. In several tumor histotypes, we demonstrated a different degree of synergism between trabectedin and PARP1 inhibitors (PARP1-Is). Independent of BRCA1/2 status, PARP1 expression dictated the degree of synergism. Namely, silenced PARP1 reduced trabectedin-PARP1-Is synergism, whereas overexpressed PARP1 increased combination efficacy. High-PARP1 expression and specific gene signatures associated with DNA damage response and repair (DDR-R) were predictive of trabectedin+PARP1-I synergy. These findings pave the way for the clinical development of this novel combination therapy, as well as evaluation of PARP1 expression and DDR-R signatures in tumor samples as predictive biomarkers of response

2017-06-12 | GSE77175 | GEO

PARP1 expression predicts and determines synergy between PARP1 inhibitors and trabectedin.

2017-06-12 | GSE76981 | GEO

Trabectedin derails transcription-coupled nucleotide excision repair to induce DNA breaks in highly transcribed genes

Project description:Most genotoxic anticancer agents fail in tumors with intact DNA repair. Therefore, trabectedin, a unique agent more toxic to cells with active DNA repair, specifically transcription-coupled nucleotide excision repair (TC-NER), provides new therapeutic opportunities. To unlock the potential of trabectedin and inform its application in precision oncology, a full mechanistic understanding of the drug’s TC-NER-dependent toxicity is needed. Here, we determined that abortive TC-NER of trabectedin-DNA adducts forms persistent single-strand breaks (SSBs) by blocking the second of the two sequential NER incisions by XPG. We mapped the 3’-hydroxyl groups of SSBs originating from the first NER incision at trabectedin lesions, recording TC-NER on a genome-wide scale. We showed that trabectedin-induced SSBs primarily occur in transcribed strands of active genes and peak near transcription start sites. Frequent SSBs were also found outside gene bodies, revealing TC-NER connection to divergent transcription from promoters. This work advances trabectedin as a tool compound for precision oncology and for studying TC-NER and transcription.

2023-12-22 | GSE245883 | GEO

Trabectedin is a novel chemotherapy agent for diffuse large B cell lymphoma

Project description:Assess the efficacy of trabectedin in two DLBCL cell lines

2018-08-22 | GSE104197 | GEO

Whole genome transcription profiling of the JN-DSCRT1 cell line treated with Trabectedin

Project description:The purpose of experiments consisted in studying the mode of action of Trabectedin in Desmoplastic Small Round Cell Tumor (DSRCT). In order to investigate the effects of Trabectedin in the expression of EWS-WT1 target genes in relation to the drug growth inhibitory effect, the JN-DSCRT-1 cell line was treated for 1 hour with 5 nM of Trabectedin. Samples were collected at 6, 12 and 24 hours after drug washout. Three biological replicates were used for each time point.

2017-01-27 | E-MTAB-4532 | biostudies-arrayexpress

Trabectedin Promotes Oncolytic Virus Antitumor Efficacy, Viral Gene Expression, and Immune Effector Function in Models of Bone Sarcoma

Project description:Trabectedin Promotes Oncolytic Virus Antitumor Efficacy, Viral Gene Expression, and Immune Effector Function in Models of Bone Sarcoma

| PRJNA1082199 | ENA

Comparison Between Gene Expression Profiles of Sensitive and Resistant Trabectedin Liposarcoma Cell Lines

Project description:Gene expression profiles of 402-91 FUS-CHOP type I cells have been compared to 402-91/ET cells made resistant to Trabectedin

2010-07-13 | GSE20350 | GEO