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Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer

ABSTRACT: Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer

PROVIDER: PRJNA952994 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24097948_1.fastq.gz	Fastqsanger.gz
	SRR24097948_2.fastq.gz	Fastqsanger.gz
	SRR24097949_1.fastq.gz	Fastqsanger.gz
	SRR24097949_2.fastq.gz	Fastqsanger.gz
	SRR24097950_1.fastq.gz	Fastqsanger.gz

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Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer

Project description:PARP inhibitor olaparib induces the formation of polyploid giant cancer cells (PGCCs) in ovarian and breast cancer cell lines, human high-grade serous ovarian cancer (HGSC)–derived organoids, and HGSC patient-derived xenografts (PDXs). Time-lapse tracking of ovarian cancer cells revealed that PGCCs primarily developed from endoreplication of cancer cells after exposure to sublethal concentrations of olaparib. PGCCs exhibited features of senescent cells but, after olaparib withdrawal, could escape senescence via restitutional multipolar endomitosis and other modes of cell division to generate mitotically competent resistant daughter cells. The contraceptive drug mifepristone blocked PGCC formation and daughter cell production. Mifepristone/olaparib combination therapy substantially reduced tumor growth in PDX models without previous olaparib exposure, while mifepristone alone decreased tumor growth in PDX models with acquired olaparib resistance. Thus, targeting PGCCs may represent a promising approach to potentiate the therapeutic response to PARPi and overcome PARPi-induced resistance.

2023-08-08 | GSE229119 | GEO

CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer

Project description:CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer

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Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer.

Project description: Not available

| S-EPMC10361597 | biostudies-literature

CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer

Project description:PARP inhibitors have demonstrated remarkable clinical efficacy in treating ovarian cancer (OV) patients with BRCA1/2 mutations. However, drug resistance inevitably limits their clinical applications and there is an urgent need for improved therapeutic strategies to enhance the clinical utility of PARP inhibitors, such as Olaparib. Here, we present compelling evidence that PARP inhibitor sensitivity is associated with cell cycle dysfunction, independent of homologous recombination deficiency (HRD) /BRCA status. Through high-throughput drug screening with a cell cycle kinase inhibitor library, we identified XL413, a potent CDC7 inhibitor, which can synergistically enhance the anti-cancer efficacy of Olaparib. Mechanistically, we demonstrate that the combined administration of XL413 and Olaparib induced considerable DNA damage and DNA replication stress, leading to increased sensitivity to Olaparib. Additionally, a robust type-I interferon response was triggered through the induction of the cGAS/STING signaling pathway. Using a murine syngeneic tumor model, we further demonstrate that the combination treatment enhanced antitumor immunity, resulting in tumor regression. Collectively, this study presents a novel treatment strategy for patients with advanced OV by combining CDC7 and PARP inhibitiors, offering a promising therapeutic approach forpatients whith limited response to PARP inhibitors.

2024-12-18 | GSE247622 | GEO

Polyploid cancer cells reveal signatures of chemotherapy relapse [scRNA-seq]

Project description:Treatment of PC3 and MDA-MB-231 cell lines with sublethal doses of docetaxel or cisplatin in vitro resulted in induction of polyploid cancer cells. Single cell copy RNA-sequencing was conducted to understand resistance of polyploid cancer cells to chemotherapy.

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Polyploid cancer cells reveal signatures of chemotherapy relapse [scDNA-seq]

Project description:Treatment of PC3 and MDA-MB-231 cell lines with sublethal doses of docetaxel or cisplatin in vitro resulted in induction of polyploid cancer cells. Single cell copy number profiling was conducted to understand resistance of polyploid cancer cells to chemotherapy.

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Polyploid Giant Cancer Cells are dependent on cholesterol for progeny formation through amitotic division

Project description:Polyploid Giant Cancer Cells (PGCC) are increasingly being studied for their role in cancer recurrence and mortality. These cells are induced in bulk cancer cell populations when under stress such as hypoxia or treatment stress (i.e. chemotherapy or radiation). PGCC utilize temporary senescence achieved via a dedifferentiation pathway to survive transient stresses, providing a seed population for later regrowth. Our previous work demonstrated a dependence on the lysosomal enzyme acid ceramidase (ASAH1) in these cells, such that they are unable to perform division without ASAH1. The pro-drug LCL521 is lysosomally targeted, fully inhibits ASAH1 activity within 5 hours, and ablates the ability of PGCC to generate progeny while permitting mitotic cancer cells to proliferate normally. We used an RNASeq approach to compare the responses of parental PPC1 prostate cancer cells and their radiation-induced PGCC counterparts to 5 hours of LCL-521 treatment. RNASeq confirmed that no major changes were triggered in parental PPC1 cells while PGCC appeared to respond as if they had undergone cholesterol depletion.

2022-06-01 | GSE195919 | GEO

CDK2 Inhibition Produces a Persistent Population of Polyploid Cancer Cells

Project description:Aneuploidy, a cancer hallmark, drives chromosomal instability, drug resistance, and clinically-aggressive tumors. Cyclin-dependent kinase 2 (CDK2) antagonism with independent inhibitors or CDK2 knock-down triggered anaphase catastrophe. This disrupts supernumerary centrosome clustering, causing multipolar division and apoptosis. Time-lapse fluorescent microscopy of FUCCI cell cycle probes transduced into aneuploid lung cancer cells revealed distinct fates of bipolar and polyploid cells after CDK2 inhibition. Apoptosis occurred in multipolar progeny but was repressed in persistent polyploid cancer cells. RNA-seq analyses after CDK2 inhibition of 4N versus 2N lung cancer cells were enriched for CDK1 pathway and KIF family members. The Cancer Genome Atlas (TCGA) analysis of lung cancers indicated CDK1 and KIF family member overexpression was associated with an unfavorable survival. Intravital microscopy of transplanted lung cancer cells in mice extended findings from the in vitro to in vivo settings. CDK2 inhibition of tumor-bearing mice produced polyploid cancer cells in vivo. These cancer cells were resistant to apoptosis and proliferated despite CDK2 inhibition. In contrast, polyploid populations were rarely detected in CDK2 inhibited human alveolar epithelial cells. These findings are translationally relevant. Combined targeting of CDK2 with CDK1 or kinesin family member antagonists should eliminate polyploid cancer cells, promote apoptosis and augment antineoplastic effects.

2025-04-06 | GSE292967 | GEO

RNA expression profiles of murine polyploid trophoblast giant cells (TGCs) from day 9.5 implantation sites.

Project description:We employed RNA-seq to transcriptionally profile a pure population of hand-dissected polyploid TGCs from embryonic day 9.5. These data provide a set of polyploid-specific TGCs transcripts that will aid in the understanding of TGCs differentiation and endoreplication. TGCs were micro-dissected from day E9.5 nine implantation sites from C57BL/6J mice. The portion of the TGCs in direct contact with the spongiotrophoblast layer and the labyrinth layer were manually removed to avoid collecting any polyploid cells from the former or multi-nucleated syncytiotrophoblast cells from the latter.

2013-04-30 | E-GEOD-45782 | biostudies-arrayexpress

RNA expression profiles of murine polyploid trophoblast giant cells (TGCs) from day 9.5 implantation sites.

2013-04-30 | GSE45782 | GEO