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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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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

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

Project description:To understand the mechanism of acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib, we induced the formation of polyploid giant cancer cells (PGCCs) in ovarian and breast cancer cell lines, high-grade serous cancer (HGSC)-derived organoids, and patient-derived xenografts (PDXs). Time-lapse tracking of ovarian cancer cells revealed that PGCCs primarily developed from endoreplication after exposure to sublethal concentrations of olaparib. PGCCs exhibited features of senescent cells but, after olaparib withdrawal, can escape senescence via restitutional multipolar endomitosis and other noncanonical modes of cell division to generate mitotically competent resistant daughter cells. The contraceptive drug mifepristone blocked PGCC formation and daughter cell formation. 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.

| S-EPMC10361597 | biostudies-literature

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

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

Project description:We employed miRNA-seq to profile all miRNAs from a pure population of hand-dissected polyploid TGCs from embryonic day 9.5. These data set of polyploid-specific TGCs microRNAs will provide insights into TGCs differentiation and endoreplication. TGCs were micro-dissected from day E9.5 nine implantation sites from C57BL/J6 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-45784 | biostudies-arrayexpress

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

2013-04-30 | GSE45784 | GEO

Targeting immunosuppressive macrophages overcomes PARP-inhibitor resistance in BRCA1-associated triple-negative breast cancer

Project description:Despite objective responses to PARP inhibition and improvements in progression-free survival compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in BRCA-associated TNBC. Through multi-omics profiling we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming driven by the sterol regulatory element-binding protein 1 (SREBP-1) pathway. Combined PARP inhibitor therapy with CSF-1R blocking antibodies significantly enhanced innate and adaptive anti-tumor immunity and extends survival in BRCA-deficient tumors in vivo and is mediated by CD8+ T-cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate combined PARP inhibition and macrophage targeting therapy induces a durable reprogramming of the tumor microenvironment, thus constituting a promising therapeutic strategy for TNBC.

2021-03-25 | PXD015804 | Pride

Murine polyploid trophoblast giant cells (TGCs) from day E9.5 implantation sites (experimental) vs E9.5 diploid embryos (control)

Project description:Array-based quantitative genome hybridization (aCGH) was performed to quantify gene copy number across the euchromatic portion of the genome of polyploid TGCs relative to embryonic diploid control cells. DNA was prepared from diploid embryonic cells and purified polyploid TGCs, labeled, and hybridized to microarrays. Experiment was performed in two biological replicates.

2013-04-30 | E-GEOD-45778 | biostudies-arrayexpress

Murine polyploid trophoblast giant cells (TGCs) from day E9.5 implantation sites (experimental) vs E9.5 diploid embryos (control)

2013-04-30 | GSE45778 | 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.

2024-09-13 | GSE270568 | GEO

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