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Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [RNA-seq]

ABSTRACT: Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [RNA-seq]

PROVIDER: PRJNA1218454 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32203700.fastq.gz	Fastqsanger.gz
	SRR32203701.fastq.gz	Fastqsanger.gz
	SRR32203702.fastq.gz	Fastqsanger.gz
	SRR32203693.fastq.gz	Fastqsanger.gz
	SRR32203694.fastq.gz	Fastqsanger.gz

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Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [RNA-seq]

Project description:Tumor evolution is one of the major mechanisms responsible for acquiring therapy-resistant and more aggressive cancer clones. Whether the tumor microenvironment through immune-mediated mechanisms might promote the development of more aggressive cancer types is crucial for the identification of additional therapeutical opportunities. Here, we identified a novel subset of tumor-associated neutrophils, defined as tumor-associated neutrophil precursors (PreNeu). These PreNeu are enriched in female highly proliferative hormone-dependent breast cancers and impair DNA repair capacity.  Mechanistically, succinate secreted by tumor-associated PreNeu inhibit homologous recombination, promoting error-prone DNA repair through non-homologous end-joining regulated by PARP-1. Consequently, breast cancer cells acquire genomic instability promoting tumor editing and progression. Selective inhibition of these pathways induces increased tumor cell killing in vitro and in vivo. Tumor-associated PreNeu score correlates with copy number alterations in highly proliferative hormone-dependent tumors from breast cancer patients. Treatment with PARP-1 inhibitors counteract the pro-tumoral effect of these neutrophils.

2025-03-18 | GSE288569 | GEO

Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [ChIP-seq]

2025-03-18 | GSE288568 | GEO

Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition.

Project description:Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition.

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Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [ChIP-seq]

Project description:Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [ChIP-seq]

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Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition.

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

2025-03-18 | GSE288570 | GEO

Project description:Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition

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ALC1 and PARP activities coordinate chromatin accessibility and viability in homologous recombination deficient cells (ATAC-seq)

Project description:The response to Poly (ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair mechanisms and the abundance of lesions that trap PARP enzymes on chromatin. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these settings. Using a CRISPR based screen, we identify the PAR-binding Snf2-like ATPase, ALC1 as a key determinant of PARPi toxicity in HR-deficient cells. ALC1 loss reduced viability of BRCA mutant cells and enhanced their sensitivity to PARPi by up to 250-fold, while overcoming several known resistance mechanisms. ALC1 loss was not epistatic to other repair pathways that execute the PARPi response. Instead, ALC1 deficiency reduced chromatin accessibility concomitant with a decrease in the association of repair factors. This resulted in an accumulation of replication associated DNA damage and a reliance on HR. These findings establish PAR-dependent chromatin remodeling as a mechanistically distinct aspect of PARPi responses, implicating ALC1 inhibition as a new approach to overcome therapeutic resistance in HR-deficient cancers.

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ALC1 and PARP activities coordinate chromatin accessibility and viability in homologous recombination deficient cells (RNA-seq)

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Amplification of mutant BRCA2 gene confers resistance to PARP inhibitor

Project description:Breast cancer gene 2 (BRCA2) deleterious mutations confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition due to its critical role in DNA repair. PARP inhibitor Olaparib is now approved and several other PARP inhibitors are now in different stages of clinical trials. Development of resistance to PARP inhibitors limits their clinical utility. The mechanism of resistance remains not fully understood. Here we show that amplification of mutant BRCA2 confers PARP inhibitor resistance. The amplification of mutant BRCA2 gene copies correlates with an increase in mutant BRCA2 expression and an increase in the levels of its interacting proteins PALB2 and RAD51. In addition, homologous recombination mediated DNA repair is rescued in these cells as evidenced by the formation of RAD51 focus formation. The overexpressed mutant BRCA2 is essential for the observed PARP inhibitor resistance because knockdown of its expression is sufficient to re-sensitize these cells to PARP inhibition. Collectively, our results indicate a new mechanism of resistance to PARP inhibitor in BRCA2 mutant cancer cells

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