IL-6 promotes drug resistance through formation of polyploid giant cancer cells and stromal fibroblast reprogramming
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ABSTRACT:
PROVIDER: PRJNA740278 | ENA |
REPOSITORIES: ENA
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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:To understand the role of polyploid giant cancer cells (PGCCs) in drug resistance and disease relapse, we examined the mRNA expression profile of PGCCs following treatment with paclitaxel 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.
| S-EPMC8481288 | biostudies-literature
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: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. 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: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 are dependent on cholesterol for progeny formation through amitotic division
| PRJNA802677 | ENA