Transcriptome Analysis of Cyclophosphamide Effects on Ovarian Development in Mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE128240 | GEO | 2020/01/01
REPOSITORIES: GEO
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Project description:Chemotherapy-induced ovarian damage and infertility are significant concerns for women of childbearing age with cancer, but the underlying mechanisms are still not fully understood. Our study revealed a close association between the loss of H3K27me3 and cyclophosphamide (CTX)-induced ovarian damage.
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Project description:Chemotherapy-induced ovarian damage and infertility are significant concerns for women of childbearing age with cancer, but the underlying mechanisms are still not fully understood. Our study revealed a close association between H3K27me3 and cyclophosphamide (CTX)-induced ovarian damage, especially in granulosa cells.
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Project description:Abnormal granulosa cells (GCs) death contributes to cyclophosphamide (CTX) -induced primary ovarian insufficiency (POI). To investigate the contribution of GCs in POI, gene profiles of GCs exposed to CTX were assessed using RNA-Seq and bioinformatics analysis. The results showed the differentially expressed genes (DEGs) are enriched in ferroptosis-related pathway, which is correlated with the upregulated Heme oxygenase 1 (HO-1) and downregulated glutathione peroxidase-4 (GPX4). Using CTX-induced cell culture (COV434 and KGN cells), the levels of iron, reactive oxygen species (ROS), lipid peroxide, mitochondrial superoxide, mitochondrial morphology and mitochondrial membrane potential (MMP) were detected by DCFDA, MitoSOX, C11-BODIPY, MitoTracker, Nonylacridine Orange (NAO), JC-1 and transmission electron microscopy respectively. The results showed that iron overload and disrupting ROS, including cytoROS, mtROS and lipROS homeostasis by HO-1 upregultion could induce ferroptosis via mitochondrial dysfunction in CTX-induced GCs. Moreover, HO-1 inhibition could suppress ferroptosis induced GPX4 depletion. This implies the role of ROS in CTX-induced ferroptosis and highlighted the effect of HO-1 modulators of improving CTX-induced ovarian damage, which may provide a theoretical basis for preventing or restoring GC and ovarian function in patients with POI.
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Project description:Certain anticancer drugs, particularly cyclophosphamide (CTX), were shown to enhance the antitumor efficacy of immunotherapy through different immunomodulatory mechanisms. A better understanding of the cellular and molecular basis of CTX-mediated immunomodulation is needed to improve the efficacy of chemoimmunotherapy. Transcript profiling and flow cytometry were used to explore CTX immune-enhancing activity in patients with hematologic malignancies. A single high-dose treatment quickly (1-2 days) induced an extensive transcriptional modulation in peripheral blood mononuclear cells, leading to the reduction of cell cycle and biosynthetic/metabolic processes and to the augmentation of transcripts related to DNA damage and cell death (p53 signaling pathway, CDKN1A, CCND3, BAX, BBC3, BID, DDB2, SESN2), of scavenger receptors involved in the recognition of death (MARCO, CD68, CD163L1, SCARB2), of antigen processing/presentation mediators (CIITA, CTSC, CTSL1, CTSZ, GLA, GAA, TPP1, NEU1, SLC11A1, LAMP-2), of T cell activation markers (CD69, OX40) and, noticeably, of a type I interferon (IFN-I) signature (OAS1, CXCL10, BAFF, IFITM2, IFI6, IRF5, IRF7, STAT2, UBE2L6, UNC93B1, ISG20L1, TYK2). Moreover, the plasma levels of IFN-I-induced proinflammatory mediators (CXCL10, CCL2, IL-8, BAFF) were increased by treatment. Accordingly, CTX preconditioning induced both monocyte and lymphocyte activation, leading to the expansion of CD14+CD16+ monocytes, of HLA-DR+, IL8RA+, MARCO+ monocytes/dendritic cells and of CD69+, OX40+, IL8RA+ lymphocytes. Altogether, these data define for the first time the immunomodulatory factors induced by CTX in humans and indicate that preconditioning chemotherapy may stimulate immunity as a consequence of danger perception associated to its cytotoxic action on blood cells, through p53 and IFN-I-related mechanisms. Four-condition experiment, Untreated (10 Biological replicates) - Cyclophosphamide-treated 1 day (10 Biological replicates) - Cyclophosphamide-treated 2 days (8 Biological replicates) - Cyclophosphamide-treated 5 days (5 Biological replicates). Each sample labeled with Cy5 and co-hybridized with Cy3-labeled M-bM-^@M-^\referenceM-bM-^@M-^] aRNA. One replicate per array.
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Project description:Low-quality oocytes directly affect fertilization and embryo developmental ability, and further contributes to infertility in women. Dasatinib and quercetin, as a senolytics, has been explored extensively in various age-related diseases. Here, we report that nano-encapsulated senolytics cocktail (D+Q) efficaciously ameliorates the the quantity and quality of follicles and oocytes in vitro and in vivo. D+Q cocktail supplementation reduces the level of ROS in aged oocytes, decreases the frequency of fragmentation, maintains the spindle integrity, rescues mislocalized cortical granules, rescues mitochondrial membrane potential and alleviates DNA damage and apoptosis in vitro. Nano-encapsulated D+Q cocktail effectively ameliorates the fertility deficits in the cyclophosphamide-induced primary ovarian failure (POF) mice model. Moreover, RNA sequencing analysis shows that D+Q cocktail improves the fecundity of POF mice by increasing development gene expression and reduces the senescence-associated secretory phenotype (SASP) accumulation. Taken together, our data show that the D+Q cocktail helps to improve assisted reproductive technology and reproductive outcomes in POF.
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Project description:Certain anticancer drugs, particularly cyclophosphamide (CTX), were shown to enhance the antitumor efficacy of immunotherapy through different immunomodulatory mechanisms. A better understanding of the cellular and molecular basis of CTX-mediated immunomodulation is needed to improve the efficacy of chemoimmunotherapy. Transcript profiling and flow cytometry were used to explore CTX immune-enhancing activity in patients with hematologic malignancies. A single high-dose treatment quickly (1-2 days) induced an extensive transcriptional modulation in peripheral blood mononuclear cells, leading to the reduction of cell cycle and biosynthetic/metabolic processes and to the augmentation of transcripts related to DNA damage and cell death (p53 signaling pathway, CDKN1A, CCND3, BAX, BBC3, BID, DDB2, SESN2), of scavenger receptors involved in the recognition of death (MARCO, CD68, CD163L1, SCARB2), of antigen processing/presentation mediators (CIITA, CTSC, CTSL1, CTSZ, GLA, GAA, TPP1, NEU1, SLC11A1, LAMP-2), of T cell activation markers (CD69, OX40) and, noticeably, of a type I interferon (IFN-I) signature (OAS1, CXCL10, BAFF, IFITM2, IFI6, IRF5, IRF7, STAT2, UBE2L6, UNC93B1, ISG20L1, TYK2). Moreover, the plasma levels of IFN-I-induced proinflammatory mediators (CXCL10, CCL2, IL-8, BAFF) were increased by treatment. Accordingly, CTX preconditioning induced both monocyte and lymphocyte activation, leading to the expansion of CD14+CD16+ monocytes, of HLA-DR+, IL8RA+, MARCO+ monocytes/dendritic cells and of CD69+, OX40+, IL8RA+ lymphocytes. Altogether, these data define for the first time the immunomodulatory factors induced by CTX in humans and indicate that preconditioning chemotherapy may stimulate immunity as a consequence of danger perception associated to its cytotoxic action on blood cells, through p53 and IFN-I-related mechanisms.
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Project description:Immune checkpoint blockade (ICB) therapy is a standard treatment option for many malignancies, but it is only effective in a subset of patients. Combination strategies to overcome resistance are promising areas of investigation. Targeting glucocorticoidinduced TNFR-related (GITR) protein with agonist antibodies has shown efficacy in preclinical models, but GITR engagement does not control growth of advanced poorly immunogenic murine tumors such as B16 melanoma and has not yielded benefit in clinical trials. The alkylating agent cyclophosphamide (CTX) preferentially depletes regulatory T cells (Tregs) and expands tumor-specific effector T cells (Teffs) via homeostatic proliferation. Additionally, CTX directly induces tumor cell death, thereby releasing antigen to prime Teffs in a lymphopenic environment where there are fewer Tregs. GITR agonism has a net inhibitory effect on Tregs and yet activates Teff. We therefore hypothesized that CTX treatment prior to GITR agonism would promote potent anti-tumor immunity. Here we show that the combination of CTX and GITR agonism robustly controls tumor growth in several clinically relevant mouse models. Mechanistically, we show that the combination therapy causes tumor cell death, clonal expansion of highly active and terminally differentiated CD8+ T cells, and depletion of regulatory T cells by AICD. Control of tumor growth was also associated with the presence of an expanded population of highly activated tumor-infiltrating oligoclonal CD8+ T cells that lead to a global contracted TCR repertoire. Our studies show that the combination of CTX and GITR agonism is a rational chemo-immunotherapeutic approach that warrants further clinical investigation.
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Project description:This SuperSeries is composed of the following subset Series: GSE27421: Mouse bone marrow cyclophosphamide treated vs untreated GSE27422: Mouse peripheral blood leukocytes cyclophosphamide treated vs untreated GSE27423: Mouse spleen cyclophosphamide treated vs untreated Refer to individual Series
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