Polyploid Giant Cancer Cells are dependent on cholesterol for progeny formation through amitotic division
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PROVIDER: PRJNA802677 | ENA |
REPOSITORIES: ENA
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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
Project description:We characterized the mouse trophoblast giant cell epigenome and gene expression profiles. We then compared these data to our data on underrepresentation in the polyploid trophoblast giant cells.
2014-05-29 | GSE50561 | GEO
Project description:We characterized regions of underrepresentation that are specific to mouse polyploid trophoblast giant cells. We performed array Comparative Genomics Hybridization (aCGH) to examine copy number variation (CNV) in mouse polyploid trophoblast giant cells (TGCs). We performed the following experiments in duplicates to examine CNV during various stages of in vivo and in vitro TGC development: e9.5 TGCs vs. embryonic controls, e11.5 TGCs vs. embryonic controls, e13.5 TGCs vs. embryonic controls, e16.5 TGCs vs. embryonic controls, as well as TGCs cultured 3, 5 and 7 days vs. 2N trophoblast stem cells. We also performed the following controls to show that underrepresentation is only found in polypoid trophoblast giant cells and not in either 2N placental cell types nor in other types of polyploid cells: 2N placenta disk vs. embryonic controls, 2N trophoblast stem cells vs. embryonic stem cells, and polyploid Megakaryocytes vs. embryonic controls. When possible, we performed arrays with the test and control samples of opposite sex (F-female, M-male), as an internal control for the array.
2014-05-29 | E-GEOD-50543 | biostudies-arrayexpress
Project description:We characterized regions of underrepresentation that are specific to mouse polyploid trophoblast giant cells.
2014-05-29 | GSE50543 | GEO
Project description:We characterized the mouse trophoblast giant cell epigenome and gene expression profiles. We then compared these data to our data on underrepresentation in the polyploid trophoblast giant cells. We profiled 5 histone modifications (+ chromatin input) using ChIP-Seq, and digital expression profiles (3' RNA-Seq) for trophoblast giant cells derived from mouse. Furthermore, we profiled digital expression profiles (3' RNA-Seq) for in vivo trophoblast giant cells samples from e9.5 wildtype mouse trophoblast giant cells. We found that underrepresented domains in trophoblast giant cells are enriched for repressive marks and anti-correlate with active marks and transcription.
2014-05-29 | E-GEOD-50561 | biostudies-arrayexpress
Project description:To understand the role of polyploid giant cancer cells (PGCCs) in drug resistance and disease relapse, we examined the mRNA expression profile of PGCCs in ovarian cancer cells. An acute activation of IL-6 dominated senescence associated secretory phenotype lasted 2-3 weeks and declined during the termination phase of polyploidy. IL-6 activates embryonic stemness during the initiation of PGCCs and can reprogram normal fibroblasts into cancer-associated fibroblasts (CAFs) via increased collagen synthesis, activation of VEGF expression, and enrichment of CAFs and the GPR77+/CD10+ fibroblast subpopulation. Blocking the IL-6 feedback loop with tocilizumab or apigenin prevented PGCC formation, attenuated embryonic stemness and the CAF phenotype, and inhibited tumor growth in a patient-derived xenograft high-grade serous ovarian carcinoma model. Thus, IL-6 derived by PGCCs is capable of reprogramming both cancer and stromal cells and contributes to the evolution and remodeling of cancer. Targeting IL-6 in PGCCs may represent a novel approach to combating drug resistance
2021-06-24 | GSE178745 | GEO
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
Project description:We profiled trophoblast stem cell replication-timing in order to compare these data to our data on underrepresented (UR) domainss in trophoblast giant cells (polyploid cells derived from 2N trophoblast stem cells). We found that UR domains are formed from late-replicating regions in tropoblast stem cells. Profile of early and late replicating regions in cultured trophoblast stem cells.
2014-05-29 | E-GEOD-50207 | biostudies-arrayexpress
Project description:We profiled trophoblast stem cell replication-timing in order to compare these data to our data on underrepresented (UR) domainss in trophoblast giant cells (polyploid cells derived from 2N trophoblast stem cells). We found that UR domains are formed from late-replicating regions in tropoblast stem cells.
2014-05-29 | GSE50207 | GEO
Project description:Polyploid giant cancer cells (PGCC) constitute a transiently senescent subpopulation of cancer cells that arises in response to stress. PGCC are capable of generating progeny via a primitive, cleavage-like cell division that is dependent on the sphingolipid enzyme acid ceramidase (ASAH1). The goal of this study was to understand differences in sphingolipid metabolism between non-polyploid and polyploid cancer cells to gain an understanding of the ASAH1-dependence in the PGCC population. Steady-state and flux analysis of sphingolipids did not support our initial hypothesis that the ASAH1 product sphingosine is rapidly converted into the pro-survival lipid sphingosine-1-phosphate. Instead, our results suggest that ASAH1 activity is important for preventing the accumulation of long chain ceramides such as C16-ceramide. We therefore determined how modulation of C16-ceramide, either through CerS6 or p53, a known PGCC suppressor and enhancer of CerS6-derived C16-ceramide, affected PGCC progeny formation. Co-expression of the CerS6 and p53 abrogated the ability of PGCC to form offspring, suggesting that the two genes form a positive feedback loop. CerS6 enhanced the effect of p53 by significantly increasing protein half-life. Our results support the idea that sphingolipid metabolism is of functional importance in PGCC and that targeting this signaling pathway has potential for clinical intervention.
| S-EPMC8125704 | biostudies-literature