Treatment with onvansertib, a specific PLK1 inhibitor, overcomes olaparib resistance in high-grade serous ovarian carcinoma patient-derived xenografts
Ontology highlight
ABSTRACT:
INSTRUMENT(S): NextSeq 500
ORGANISM(S): Mus musculus
SUBMITTER: Luca Guarrera
PROVIDER: E-MTAB-13055 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:We hypothesized that the transcriptome of primary cultures of morphologically normal ovarian surface epithelial cells could be altered by the presence of a heterozygous BRCA1 or BRCA2 mutation. We aimed to discover early events associated to ovarian carcinogenesis, which could represent putative targets for preventive strategies of this silent killer tumor. We identified the first molecular signature associated with French Canadian BRCA1 or BRCA2 founder mutations in morphologically normal ovarian epithelial cells. We discovered that wild-type and mutated BRCA2 allelic transcripts were expressed not only in morphologically normal but also in tumor cells from 8765delAG BRCA2 carriers. Further analysis of morphologically normal ovarian and tumor cells from C4446T BRCA1 carriers lead to the same observation. Our data support the idea that one single hit in BRCA1 or BRCA2 is sufficient to alter the transcriptome of phenotypically normal ovarian epithelial cell. The highest level of BRCA2 mutated allele transcript expression was measured in cells originating from the most aggressive ovarian tumor. The penetrance of the mutation and the aggressiveness of the related tumor could depend on a dosage effect of the mutated allele transcript. We studied the molecular profiles associated with 5 a priori classes of samples : 4 non-familial morphologically normal ovarian surface epithelium (NOSEs) : NM class, 2 BRCA1-mutated NOSEs : M1 class, 3 BRCA2-mutated NOSEs : M2 class, 3 BRCA1-mutated ovarian tumor cells (TOVs) : TM1 class and one BRCA2-mutated TOV :TM2 class. No technical replicates were included in this study. The following contrasts were computed : NM vs. M1, NM vs. M2, M1 vs. M2, M1 vs. TM1 and M (M1 union M2) vs. TM (TM1 union TM2).
2012-06-14 | E-GEOD-34928 | biostudies-arrayexpress
Project description:Ovarian cancer is a major cause of cancer mortality among women largely due to late diagnosis of advanced stage metastatic disease. More extensive molecular analysis of metastatic ovarian cancer is needed to identify post-translational modifications of proteins particularly associated with metastatic disease so that we can better understand the metastatic process and identify potential therapeutic targets. Proteins are the target of many recently developed cancer treatments, but an often neglected aspect of biomarker discovery is protein glycosylation, especially those involving tumor-associated carbohydrate antigens (TACAs) such as sialyl-Lewis(x) (SLe(x) and sialyl-Lewis(a) (SLe(a), which have been identified in various cancers. Although it is already known that considerable changes in protein glycosylation are major contributors to the initiation, progression and metastasis of tumors, specifics about glycosylation changes particularly important to the metastatic process are still lacking. In this report we describe the results of a combined glycomic and proteomic study of metastatic ovarian cancer (OC) ascites fluids. Glycoproteins in ascites fluid were enriched by affinity binding to lectins (ConA or WGA) and other affinity matrices. Separate glycomic and proteomic analyses were performed as well as glycopeptide analyses. Relative abundances of different N-glycan groups and proteins were identified from original ascites fluids and corresponding lectin bound samples. Levels of biomarkers CA125, MUC1 and fibronectin were also monitored in these samples by Western blot analysis. N-glycan analysis of ascites fluids showed the presence of large, highly fucosylated and sialylated, complex and hybrid glycans, some of which were not observed in normal serum. Proteins in OC ascites that were more abundant or not present in the serum control, were haptoglobin, fibronectin, lumican, fibulin, hemopexin, ceruloplasmin, alpha-1-antitrypsin and alpha-1-antichymotrypsin. Glycopeptide analysis identified N- and O-glycans in clusterin, hemopexin, and fibulin that were present in OC ascites.
2016-08-15 | PXD003794 | Pride
Project description:Regulatory T (Treg) cells play an important role in the induction and maintenance of peripheral tolerance. Treg cells also suppress a variety of other immune responses, including anti-tumor and alloimmune responses. We have previously reported that tumor-activated Treg cells express granzyme B and that granzyme B is important for Treg cell-mediated suppression of anti-tumor immune responses (GSE13409). Here, we report that allogeneic mismatch also induces the expression of granzyme B. Granzyme B-deficient mice challenged with fully mismatched allogeneic P815 mastocytoma cells have markedly improved survival compared to WT and other granzyme- or perforin-deficient mice, suggesting an immunoregulatory role for granzyme B in this setting. Treg cells harvested from the tumor environment of P815-challenged mice express granzyme B. Treg cells also express granzyme B in vitro during mixed lymphocyte reactions and in vivo in a mouse model of graft-versus-host disease (GVHD). However, in contrast to findings from our previously published tumor model, granzyme B is not required for the suppression of effector T cell (Teff) proliferation in in vitro Treg suppression assays stimulated by either Concanavalin A or allogeneic antigen presenting cells. Additionally, in an ex vivo assay, sort-purified in vivo-activated CD4+Foxp3+ Treg cells from mice with active GVHD -- under conditions known to induce granzyme B expression in Treg cells -- suppressed Teff cell proliferation in a granzyme B-independent manner. Adoptive transfer of naive granzyme B-deficient CD4+CD25+ Treg cells into a mouse model of GVHD rescued hosts from lethatlity equivalently to naive wild-type Treg cells. Serum analysis of GVHD-associated cytokine production in these recipients also demonstrated that Treg cells suppressed production of IL-2, IL-4, IL-5, GM-CSF, and IFN-gamma in a granzyme B-independent manner. In order to determine whether the context in which Treg cells are activated alters the intrinsic properties of Treg cells, we used Foxp3 reporter mice to obtain gene expression profiles of CD4+Foxp3+ Treg cells purifed from naive resting spleens, spleens from mice with acute GVHD, and from ascites fluid of mice challenged intraperitoneally with allogeneic P815 tumor cells. Unsupervised analyses revealed distinct activation signatures of Treg cells among the 3 experimental groups. Taken together, these findings demonstrate that granzyme B is not required for Treg cell-mediated suppression of GVHD, which is in contrast to what we have previously reported for Treg cell function in the setting of tumor challenge. Cell intrinsic differences could partially account for these differential phenotypes. These data also suggest the therapeutic potential of targeting specific Treg cell suppressive functions in order to segregate GVHD and graft-versus-tumor effector functions. Experiment Overall Design: Six replicates of Naive CD4+Foxp3+ Treg cells were purified from resting spleens, five replicates of allogeneic tumor-activated Treg cells and three samples of GVHD-activated Treg cells. Experiment Overall Design: Naive reps 1-3 are controls for the GVHD-activated samples. Experiment Overall Design: Naive reps 4-6 are controls for the Allogeneic tumor-activated samples.
2009-09-15 | E-GEOD-16210 | biostudies-arrayexpress
Project description:This data was used to determine levels of BRCA1 and BRCA2 in primary human leukemia samples. Samples were determined to be high BRCA1 and/or BRCA2 or low BRCA1 and/or BRAC2. This data was used to determine levels of BRCA1 and BRCA2 in primary human leukemia samples. Samples were determined to be high BRCA1 and/or BRCA2 or low BRCA1 and/or BRAC2.
2013-07-06 | GSE48558 | GEO
Project description:The objective of this study was to identify the molecular mechanisms and biological pathways associated with the anticancer effects of flaxseed (richest plant source of Omega-3 fatty acid) in laying hen model of ovarian cancer. Study shows a significant reduction in the severity of the disease and increased survival of the laying hens fed with flaxseed. 2 X 2 condition experiment, Diet (Control & Flaxseed fed) and Tissue (Normal & Cancer). Biological replicates: 6 control normal replicates, 6 control cancer replicates, 6 flaxseed normal replicates and 6 flaxseed cancer replicates.
2015-05-18 | E-GEOD-40376 | biostudies-arrayexpress
Project description:Approximately 5% of all breast cancers can be attributed to an inherited mutation in one of two cancer susceptibility genes, BRCA1 and BRCA2. We searched for genes that have the potential to distinguish healthy BRCA1 and BRCA2 mutation carriers from non-carriers based on differences in expression profiling. Using expression microarrays we compared gene expression of irradiated lymphocytes from BRCA1 and BRCA2 mutation carriers versus control non-carriers. We identified 137 probe sets in BRCA1 carriers and 1345 in BRCA2 carriers with differential gene expression. Gene Ontology analysis revealed that most of these genes relate to regulation pathways of DNA repair processes, cell cycle regulation and apoptosis. Real-time PCR was performed on the 36 genes which were most prominently differentially expressed in the microarray assay; 21 genes were shown to be significantly differentially expressed in BRCA1 or BRCA2 mutation carriers as compared to controls (p<0.05). Based on a validation study with 40 mutation carriers and 17 non-carriers, a multiplex model that included six or more coincidental genes of 18 selected genes was constructed in order to predict the risk of carrying a mutation. The results using this model showed sensitivity 95% and specificity 88%. In summary, our study provides insight into the biological effect of heterozygous mutations in BRCA1 and BRCA2 genes in response to ionizing irradiation induced DNA damage. We also suggest a set of 18 genes that can be used as a prediction and screening tool for BRCA1 or BRCA2 mutational carriers by using easily obtained lymphocytes. Using expression microarrays we compared gene expression of irradiated lymphocytes from BRCA1 and BRCA2 mutation carriers versus control non-carriers Fresh blood samples were obtained from 9 BRCA1 and 8 BRCA2 mutation carriers and 9 mutation-negative women. Lymphocytes were collected from fresh blood samples, and RNA was extracted one hour after γ-irradiation
2013-01-10 | E-GEOD-39976 | biostudies-arrayexpress
Project description:Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. On the basis of its histopathology and molecular-genomic changes ovarian cancer has been divided into subtypes, each with distinct biology and outcome. The aim of this study was to develop a panel of patient-derived EOC-xenografts that recapitulate the molecular and biological heterogeneity of human ovarian cancer. Thirty-four EOC-xenografts were successfully established, either subcutaneously or intraperitoneally, in nude mice. The xenografts were histologically similar to the corresponding patient tumor and comprised all the major ovarian cancer subtypes. After orthotopic transplantation in the bursa of the mouse ovary, they disseminate into the organs of the peritoneal cavity and produce ascites, typical of ovarian cancer. Gene expression analysis and mutation status indicated a high degree of similarity with the original patient and discriminate different subsets of xenografts. They were very responsive, responsive and resistant to cisplatin, resembling the clinical situation in ovarian cancer. This panel of patient-derived EOC-xenografts that recapitulate the recently type I and type II classification serves to study the biology of ovarian cancer, identify tumor-specific molecular markers and develop novel treatment modalities. EOC-xenografts collected from subcutis, abdominal masses and ascitic fluid of mice engrafted with tumors at different passages (from 1 to 6) and from patient specimens, underwent one-color microarray-based gene expression profiling. To assess the amount of human- and mouse-derived cells in the xenograft tumors, total RNA was evaluated by species specific qPCR assays for beta actin. Only samples with a human RNA content > 75% were analyzed. Nine patient specimens and 62 xenograft samples (representing 29 EOC-xenograft models) underwent gene expression analysis with SurePrint G3 Human GE V2 8x60K microarrays.
2015-01-07 | E-GEOD-56920 | biostudies-arrayexpress
Project description:Inactivating germline BRCA1 and BRCA2 mutations confer a defect in homologous recombination DNA repair which was found to leave traces in tumor DNA copy number aberration (CNA) profiles. In analogy to previously trained breast cancer CNA classifiers that predicted association with BRCA1 and BRCA2 mutated cancer and benefit of high dose double strand break inducing chemotherapy, we trained BRCA1 and BRCA2 classifiers on CNA profiles of 50 BRCA1 mutated, 10 BRCA2 mutated and 13 non-familial ovarian cancers and investigated whether tumor type and mutation type independent classifiers could be trained. The cross validated area under the curve of the receiver/operator characteristic curve of ovarian cancer BRCA1 and BRCA2 classifiers were 0.67 (95% CI: 0.55-0.78) and 0.91 (95% CI: 0.79-1). These classifiers identified the majority of the samples with germline and somatic BRCA1 and BRCA2 mutations and BRCA1 promoter hypermethylation in the Cancer Genome Atlas (TCGA) dataset. Combining tumor type or mutated gene did not yield higher AUCs than single gene classifiers, although the ovarian BRCA1+BRCA2 classifier identified most BRCA1 and -2 mutated cases, including those in the TCGA dataset, and a combined breast and ovarian cancer BRCA1 classifier may improve response prediction to double strand break inducing chemotherapy.
2021-12-31 | GSE111688 | GEO
Project description:Molecular Profiling of BRCA1-and BRCA2-associated Breast Cancers Identifies FGFR2 as a Gene More Highly Expressed in BRCA2-associated Tumors BRCA1- and BRCA2-associated tumors have many morphologic characteristics in common, but appear to have distinct molecular signatures. BRCA1-associated tumors are predominantly basal-like cancers, whereas BRCA2-associated tumors have a predominant luminal-like phenotype. These two molecular signatures reflect in part the two cell types, basal/myoepithelial and luminal, found in the terminal duct lobular unit of the breast. To elucidate novel genes involved in these two spectra of breast cancer tumorigenesis we performed global gene expression analysis on breast tumors from germline BRCA1 and BRCA2 mutation carriers. Breast tumor RNAs from 7 germline BRCA1 and 6 germline BRCA2 carriers were profiled using UHN human 19K cDNA microarrays. Supervised univariate analyses were conducted to identify genes differentially expressed between BRCA1 and BRCA2-associated tumors. Selected discriminatory genes were validated using real time reverse transcription polymerase chain reaction (RT-PCR) in the tumor RNAs, and/or by immunohistochemistry (IHC) or by in situ hybridization (ISH) on tissue microarrays (TMAs) containing an independent set of 58 BRCA1 and 64 BRCA2-associated tumors. Genes more highly expressed in BRCA1-associated tumors included stathmin/oncoprotein 18, osteopontin, TGFß2 and Jagged 1 in addition to genes previously identified as characteristic of basal-like breast cancers. Genes more highly expressed in BRCA2-associated tumors had functions related to transcription, signal transduction (particularly MAPK signaling), cell proliferation, cell adhesion and extracellular matrix remodeling. BRCA2-associated cancers were characterized by the higher relative expression of amongst others, FGF1 and FGFR2. Tissue microarrays were used to validate the expression of FGFR2 protein by immunohistochemistry and Jagged 1 expression by in situ hybridization. BRCA2-associated cancers expressed higher levels of FGFR2 protein than BRCA1-associated cancers (p=0.004); whereas BRCA1-associated tumors exhibited elevated levels of Jagged1 mRNA compared to BRCA2-associated cancers (p=0.02). FGFR2 and FGF1 were more highly expressed in BRCA2-associated cancers compared with BRCA1-associated breast cancers, suggesting the existence of an autocrine or paracrine stimulatory loop. In addition to corroborating the basal-like signature of BRCA1-associated tumors, we identified osteopontin, stathmin/oncoprotein 18, TGFβ2, and Jagged 1 as being more highly expressed in BRCA1-associated tumors. Keywords: Gene expression profiling, genetic comparison
2008-09-30 | GSE9483 | GEO
Project description:Use of DNA damaging agents and RNA pooling to assess expression profiles associated with BRCA1 and BRCA2 mutation status in familial breast cancer patients Background: A large number of rare sequence variants of unknown clinical significance have been identified in the breast cancer susceptibility genes, BRCA1 and BRCA2. Determining the functional effect of these variants as well as their role in breast cancer susceptibility can be challenging using current classification methods. Methodology/Principal Findings: To identify predictors of pathogenic mutation status in familial breast cancer patients, we explored the use of gene expression arrays to assess the effect of two DNA damaging agents (irradiation and mitomycin C) on cellular response in relation to BRCA1 and BRCA2 mutation status. A range of regimes were used to treat 27 lymphoblastoid cell-lines (LCLs) derived from affected women in high-risk breast cancer families (nine BRCA1, nine BRCA2, and nine non-BRCA1/2 or BRCAX individuals) and nine LCLs from healthy individuals. Using an RNA pooling strategy, we found that treating LCLs with 1.2 μM mitomycin C and measuring the gene expression profiles 1 hour post-treatment had the greatest potential to discriminate BRCA1, BRCA2 and BRCAX mutation status. A classifier was built using the expression profile of nine QRT-PCR validated genes that were associated with BRCA1, BRCA2 and BRCAX status in RNA pools. These nine genes could distinguish BRCA1 from BRCA2 carriers with 83% accuracy in individual samples, but three-way analysis for BRCA1, BRCA2 and BRCAX had a maximum of 59% prediction accuracy. Conclusions/Significance: Our results suggest that, compared to BRCA1 and BRCA2 mutation carriers, non-BRCA1/2 (BRCAX) individuals are genetically heterogeneous. This study also demonstrates the effectiveness of RNA pools to compare the expression profiles of cell-lines from BRCA1, BRCA2 and BRCAX cases after treatment with irradiation and mitomycin C as a method to prioritize treatment regimes for detailed downstream expression analysis.
2010-01-20 | GSE17764 | GEO