Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1099879 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:End-stage breast cancers are clonally heterogeneous and harbor many poorly-understood treatment resistance mechanisms. We therefore established multiple Patient-Derived-Xenograft (PDX) models to study genomic events driving advanced disease. Comparative whole-genome sequencing of paired primary tumors and their PDX models demonstrated that PDX retain the vast majority of the structural variations and copy number aberrations seen within the originating tumor, and with high fidelity. Variant allele fractions (VAF) were preserved, even for rare mutations. Clonal representation is therefore a transplantable phenotype, indicating that genomic heterogeneity can be regulated in a tumor-autonomous mechanism, indifferent to host immune status. Mutations and gene rearrangements were documented in the ESR1 gene in three of five sequenced luminal PDX/progenitor tumor pairs (amplification, point mutation and translocation), and were associated with clinical endocrine response phenotypes, differential PDX estradiol responsiveness and all induced estradiol-independent growth in standard cell lines. PDX models are therefore a significant new tool for fundamental studies on the molecular basis for resistance to endocrine treatment in advanced breast cancer. reference x sample
2013-12-22 | E-GEOD-46604 | biostudies-arrayexpress
Project description:Most triple negative breast cancers (TNBCs) are aggressively metastatic with a high degree of intratumoral heterogeneity. We employed patient-derived xenograft models established from the breast tumors of patients with treatment-naïve metastatic TNBC to study clonal dynamics during metastasis. Genomic sequencing coupled with high-complexity barcode-mediated clonal tracking revealed robust alterations in clonal architecture between primary tumors and corresponding metastases that were deterministic rather than stochastic. The presence of numerous rare subclones in each metastatic lesion demonstrated that polyclonal seeding occurred and that heterogeneous populations of low-abundance clones were maintained in metastases. An identical population of subclones was enriched in lung, liver, and brain metastases, demonstrating that primary tumor clones harbor properties enabling them to seed and thrive in multiple organ sites. Further, clones that dominated multi-organ metastases shared a genomic lineage. Thus, intrinsic properties of rare primary tumor subclones enable the seeding and colonization of metastases in multiple organ sites.
2018-12-11 | GSE120753 | GEO
Project description:End-stage breast cancers are clonally heterogeneous and harbor many poorly-understood treatment resistance mechanisms. We therefore established multiple Patient-Derived-Xenograft (PDX) models to study genomic events driving advanced disease. Comparative whole-genome sequencing of paired primary tumors and their PDX models demonstrated that PDX retain the vast majority of the structural variations and copy number aberrations seen within the originating tumor, and with high fidelity. Variant allele fractions (VAF) were preserved, even for rare mutations. Clonal representation is therefore a transplantable phenotype, indicating that genomic heterogeneity can be regulated in a tumor-autonomous mechanism, indifferent to host immune status. Mutations and gene rearrangements were documented in the ESR1 gene in three of five sequenced luminal PDX/progenitor tumor pairs (amplification, point mutation and translocation), and were associated with clinical endocrine response phenotypes, differential PDX estradiol responsiveness and all induced estradiol-independent growth in standard cell lines. PDX models are therefore a significant new tool for fundamental studies on the molecular basis for resistance to endocrine treatment in advanced breast cancer.
2013-12-22 | GSE46604 | 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:Illumina Infinium MethylationEPIC Beadchip was used to obtain DNA methylation profiles across 850000 CpGsites in nine different breast cancer PDX models. Docetaxel resistant and residual disease PDX models were also analyzed
2019-07-18 | GSE110184 | GEO
Project description:Introduction: microRNAs are promising candidate breast cancer biomarkers due to their cancer-specific expression profiles. However, efforts to develop circulating breast cancer biomarkers are challenged by the heterogeneity of microRNAs in the blood. To overcome this challenge, we aimed to develop a molecular profile of microRNAs specifically secreted from breast cancer cells. Our first step towards this direction relates to capturing and analyzing the contents of exosomes, which are small secretory vesicles that selectively encapsulate microRNAs indicative of their cell of origin. To our knowledge, circulating exosome microRNAs have not been well evaluated as biomarkers for breast cancer diagnosis or monitoring. Methods: Exosomes were collected from the conditioned media of human breast cancer cell lines, mouse plasma of patient-derived orthotopic xenograft models (PDX), and human plasma samples. Exosomes were verified by electron microscopy, nanoparticle tracking analysis, and western blot. Cellular and exosome microRNAs from breast cancer cell lines were profiled by next-generation small RNA sequencing. Plasma exosome microRNA expression was analyzed by qRT-PCR analysis. Results: Small RNA sequencing and qRT-PCR analysis showed that several microRNAs are selectively encapsulated or highly enriched in breast cancer exosomes. Importantly, the selectively enriched exosome microRNA, human miR-1246, was detected at significantly higher levels in exosomes isolated from PDX mouse plasma, indicating that tumor exosome microRNAs are released into the circulation and can serve as plasma biomarkers for breast cancer. This observation was extended to human plasma samples where miR-1246 and miR-21 were detected at significantly higher levels in the plasma exosomes of 16 breast cancer patients as compared to the plasma exosomes of healthy control subjects. Receiver Operating Characteristic (ROC) curve analysis indicated that the combination of plasma exosome miR-1246 and miR-21 levels is a better indicator of breast cancer than their individual levels. Conclusions: Our results demonstrate that certain microRNA species, such as miR-21 and miR-1246, are selectively enriched in human breast cancer exosomes and significantly elevated in the plasma of breast cancer patients. These findings indicate a potential new strategy to selectively analyze plasma breast cancer microRNAs indicative of the presence of breast cancer.
2016-09-12 | GSE83669 | GEO
Project description:RNA-Seq and a species-specific mapping strategy were used to profile the human and mouse transcriptomes of tumour samples taken from 79 PDX models representing multiple cancer types (19 x breast, 37 x lung, 8 x colorectal, 7 x ovarian, 3 x endometrial, 2 x pancreatic, 2 x ampullary, 1 x leukaemia).
2016-03-01 | E-MTAB-3980 | biostudies-arrayexpress
Project description:Breast cancer cell lines from PDX models
2020-06-29 | GSE146024 | GEO
Project description:It is elusive whether clonal selection of tumor cells in response to ionizing radiation (IR) is a deterministic or stochastic process. With high resolution clonal barcoding and tracking of over 400.000 HNSCC patient-derived tumor cells the clonal dynamics of tumor cells in response to IR was analysed. Fractionated IR induced a strong selective pressure for clonal reduction. This significantly exceeded uniform clonal survival probabilities indicative for a strong clone-to clone difference within tumor cells. Survival to IR is driven by a deterministic clonal selection of a smaller population which commonly survives radiation, while increased clonogenic capacity is a result of clonal competition of cells which have been selected stochastically. The ratio of these parameters is amenable to radiation sensitivity which correlates to prognostic biomarkers of HNSCC. Evidence for the existence of a rare subpopulation with an intrinsically radiation resistant phenotype was found at a frequency of 0.6-3.3%. With cellular barcoding we introduce a novel functional heterogeneity associated qualitative readout for evaluating the contribution of stochastic and deterministic clonal selection processes in response to IR.
2021-09-07 | E-MTAB-9693 | biostudies-arrayexpress
Project description:To characterize Homologous recombination deficiency (BRCAness) in triple-negative breast cancer PDX models genomic signature was utilized. After normalization using Genotyping Console we obtained absolute copy number profiles using the GAP software (Popova et al, Genome Biol, 2009). The number of Large-scale State Transitions (LSTs) was used to annotate PDX as BRCAness or not (Popova et al, Cancer Res 2012).
2020-01-01 | E-MTAB-8654 | biostudies-arrayexpress