Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA319811 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3457750.fastq.gz | Fastqsanger.gz | |||
| SRR3457751.fastq.gz | Fastqsanger.gz | |||
| SRR3457752.fastq.gz | Fastqsanger.gz | |||
| SRR3457753.fastq.gz | Fastqsanger.gz | |||
| SRR3457754.fastq.gz | Fastqsanger.gz |
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Project description:To gain insights into tumor heterogeneity in anti-cancer drug responses of patient-derived xenograft models of HER2+ breast cancer brain metastases, we performed transcriptome gene expression profiling by Ion AmpliSeq™ Transcriptome sequencing that targets more than 20,000 human genes. Our data found that all anti-cancer drugs responders have significantly higher expression levels of AKT-mTOR-dependent signature genes as compared to the non-responders, suggesting that most HER2+ breast cancer brain metastases are depend on the AKT-mTOR pathway
2016-06-06 | GSE80722 | GEO
Project description:<p>We have developed orthotopic patient-derived xenograft models of HER2 positive breast cancer metastasized into the brain of patients to test novel therapeutic strategies. In this study, we identified a novel combinatorial therapeutic strategy that has resulted in a durable remission and markedly increased overall survival in majority of patient-derived xenograft (PDX) models tested. We performed whole exome sequencing analysis of these PDX tumors and their matched blood and patient samples to investigate drug sensitive and resistance mechanisms. Our sequencing data revealed an interesting association of genotyping and phenotyping with tumors responses to drug treatment.</p>
| phs001063 | dbGaP
Project description:Brain metastases are an increasing burden among breast cancer patients, particularly for those with HER2+ and triple negative (TN) subtypes. Mechanistic insight into the pathophysiology of brain metastases and preclinical validation of therapies has relied almost exclusively on intracardiac injection of brain-homing cells derived from highly aggressive TN MDA-MB-231 and HER2+ BT474 breast cancer cell lines. Yet, these well characterized models are far from representing the tumor heterogeneity observed clinically and, due to their fast progression in vivo, their suitability to validate therapies for established brain metastasis remains limited. The goal of this study was to develop and characterize novel human brain metastasis breast cancer patient-derived xenografts (BM-PDXs) to study the biology of brain metastasis and to serve as tools for testing novel therapeutic approaches. We obtained freshly resected brain metastases from consenting donors with breast cancer. Tissue was immediately implanted in the mammary fat pad of female immunocompromised mice and expanded as BM-PDXs. Brain metastases from 3/4 (75%) TN, 1/1 (100%) estrogen receptor positive (ER+), and 5/9 (55.5%) HER2+ clinical subtypes were established as transplantable BM-PDXs. To facilitate tracking of metastatic dissemination using BM-PDXs, we labeled PDX-dissociated cells with EGFP-luciferase followed by re-implantation in mice, and generated a BM-derived cell line (F2-7). Immunohistologic analyses demonstrated that parental and labeled BM-PDXs retained expression of critical clinical markers such as ER, progesterone receptor (PR), epidermal growth factor receptor (EGFR), HER2 and the basal cell marker cytokeratin 5 (CK5). Similarly, RNA sequencing analysis showed clustering of parental, labeled BM-PDXs and their corresponding cell line derivative. Intracardiac injection of dissociated cells from BM-E22-1, resulted in MRI-detectable macrometastases in 4/8 (50%) and micrometastases (8/8) (100%) mice, suggesting that BM-PDXs remain capable of colonizing the brain at high frequencies. Brain metastases developed 8 to 12 weeks after ic injection, located to the brain parenchyma, grew around blood vessels and elicited astroglia activation characteristic of breast cancer brain metastasis. These novel BM-PDXs represent heterogeneous and clinically relevant models to study mechanisms of brain metastatic colonization, with the added benefit of a slower progression rate that makes them suitable for preclinical testing of drugs in therapeutic settings.
2018-02-14 | GSE104020 | GEO
Project description:Background: Central nervous system (CNS) metastases represent a major problem in the treatment of HER2-positive breast cancer due to the disappointing efficacy of HER2-targeted therapies in the brain microenvironment. The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. Here, we tested the hypothesis that T-DM1 could overcome trastuzumab resistance in preclinical models of brain metastases. Methods: We treated mice bearing BT474 or MDA-MB-361 tumors in the CNS (N=9-11 per group), or cancer cells grown in organotypic brain slice cultures with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, and HER2 signaling. All statistical tests were two-sided. Results: T-DM1 significantly delayed the growth of HER2-positive breast cancer brain metastases compared to trastuzumab. These findings were consistent between HER2-driven and PI3K-driven tumors. The activity of T-DM1 resulted in a striking survival benefit (median survival for BT474 tumors: 28d for trastuzumab vs 112d for T-DM1, HR=6.2, 95% CI=6.1 to 85.84; P<.001). No difference in drug distribution and HER2-signaling was revealed between the two groups. However, T-DM1 led to a significant increase in tumor cell apoptosis (One-way ANOVA for ApopTag, p<.001), which was associated with mitotic catastrophe. Conclusions: T-DM1 can overcome resistance to trastuzumab therapy in HER2-driven and PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component. Clinical investigation of T-DM1 for patients with CNS metastases from HER2-positive breast cancer is warranted. Comparison of trastuzumab (n=4) and TDM-1 (n=4) treated BT-474 human breast carcinoma cells growing in murine brain
2015-11-09 | E-GEOD-69042 | biostudies-arrayexpress
Project description:Translational breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. In an effort to overcome these limitations, we propagated a cohort of human breast tumors grown in the mammary fat pad of SCID/Beige and NOD/SCID/IL2?-receptor null (NSG) two relatively new immunocompromised mouse models, under a series of transplant conditions. Both models yielded stably transplantable xenografts relatively high rates compared with previously available immunocompromised mice. Xenograft lines were established directly from breast cancer patient samples, without intervening culture in vitro, using the epithelium-free mammary fat pad as the transplantation site. Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 35 stably transplantable xenograft lines representing 27 patients were established, using pre-treatment, mid-treatment, and/or post-treatment samples. Most patients yielding xenografts were “triple-negative” (ER-PR-HER2-) (n=21). However, we were able to establish lines from three ER-PR-HER2+ patients, one ER+PR-HER2-, one ER+PR+HER2- and one “triple-positive” (ER+PR+HER2+) patient. Serially passaged xenografts show biological consistency with the tumor of origin at the histopathology level, and remarkable stability across multiple transplant generations at the genomic, transcriptomic, and proteomic levels. Of the 27 patients represented, xenografts derived from 13 patients showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource, and should prove useful for preclinical evaluation of experimental therapeutics. reference x sample
2013-06-25 | E-GEOD-34412 | biostudies-arrayexpress
Project description:Purpose: There is an unmet clinical need for biomarkers to identify breast cancer patients who are at increased risk of developing brain metastases. The objective is to identify gene signatures and biological pathways associated with HER2+ brain metastasis. Experimental Design: Gene expression of 19 HER2+ breast cancer brain metastases was compared with HER2+ nonmetastatic primary tumors. Gene Set Enrichment Analysis was used to identify a signature, which was evaluated for correlation with BRCA1 mutation status and clinical outcome using published microarray datasets and for correlation with pharmacological inhibition by a PARP inhibitor and temozolomide using published microarray datasets of breast cancer cell lines. Results: A BRCA1 Deficient-Like (BD-L) gene signature is significantly correlated with HER2+ metastases in both our and an independent cohort. BD-L signature is enriched in BRCA1 mutation carrier primary tumors and HER2-/ER- sporadic tumors, but high values are found in a subset of ER+ and HER2+ tumors. Elevated BD-L signature in primary tumors is associated with increased risk of overall relapse, brain relapse, and decreased survival. The BD-L signature correlates with pharmacologic response to PARP inhibitor and temozolomide in two independent microarray datasets, and the signature outperformed four published gene signatures of BRCA1/2 deficiency. Conclusions: The BD-L signature is enriched in breast cancer brain metastases and identifies a subset of primary tumors with increased propensity for brain metastasis. Furthermore, this signature may serve as a biomarker to identify sporadic breast cancer patients who could benefit from a therapeutic combination of PARP inhibitor and temozolomide. Gene expression of 19 HER2+ human breast cancer brain metastases was compared with gene expression of 19 HER2+ nonmetastatic primary human breast tumors.
2014-04-24 | E-GEOD-43837 | biostudies-arrayexpress
Project description:Breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. To overcome these limitations, we propagated a cohort of human breast tumors grown in the epithelium-free mammary fat pad of SCID/Beige and NOD/SCID/IL2γ-receptor null (NSG) mice, under a series of transplant conditions. Both models yielded stably transplantable xenografts at comparably high rates (~23% and ~19%, respectively). Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 32 stably transplantable xenograft lines were established, representing unique 25 patients. Most tumors yielding xenografts were “triple-negative” (ER-PR-HER2+) (n=19). However, we established lines from three ER-PR-HER2+ tumors, one ER+PR-HER2-, one ER+PR+HER2- and one “triple-positive” (ER+PR+HER2+) tumor. Serially passaged xenografts show biological consistency with the tumor of origin, are phenotypic stability across multiple transplant generations at the histological, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses. Xenografts representing 12 patients, including two ER+ lines, showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource for preclinical studies investigating treatment response and metastasis. The study was designed to determine how stable patient-derived xenografts are across multiple transplant generations in mice, and to determine how closely xenografts established with pre-treatment samples cluster with xenografts established with post-treatment samples. Overall, pre-treatment and post-treatment samples derived from the same patient cluster together, and multiple transplant generations of xenografts derived from an individual patient cluster together.
2013-05-30 | E-GEOD-46106 | biostudies-arrayexpress
Project description:Background: Central nervous system (CNS) metastases represent a major problem in the treatment of HER2-positive breast cancer due to the disappointing efficacy of HER2-targeted therapies in the brain microenvironment. The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. Here, we tested the hypothesis that T-DM1 could overcome trastuzumab resistance in preclinical models of brain metastases. Methods: We treated mice bearing BT474 or MDA-MB-361 tumors in the CNS (N=9-11 per group), or cancer cells grown in organotypic brain slice cultures with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, and HER2 signaling. All statistical tests were two-sided. Results: T-DM1 significantly delayed the growth of HER2-positive breast cancer brain metastases compared to trastuzumab. These findings were consistent between HER2-driven and PI3K-driven tumors. The activity of T-DM1 resulted in a striking survival benefit (median survival for BT474 tumors: 28d for trastuzumab vs 112d for T-DM1, HR=6.2, 95% CI=6.1 to 85.84; P<.001). No difference in drug distribution and HER2-signaling was revealed between the two groups. However, T-DM1 led to a significant increase in tumor cell apoptosis (One-way ANOVA for ApopTag, p<.001), which was associated with mitotic catastrophe. Conclusions: T-DM1 can overcome resistance to trastuzumab therapy in HER2-driven and PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component. Clinical investigation of T-DM1 for patients with CNS metastases from HER2-positive breast cancer is warranted.
2015-11-09 | GSE69042 | GEO
Project description:AXL is activated by its ligand GAS6 and is expressed in triple-negative breast cancer cells. We report that AXL is also detected in HER2+ breast cancer specimens where its expression correlates with poor patients’ survival. Using murine models of HER2+ breast cancer, AXL, but not Gas6, was found essential for metastasis. We determined that AXL is required for intravasation, extravasation and growth at the metastatic site. AXL is expressed in HER2+ cancers displaying EMT signatures and contributes to sustain EMT in murine tumors. Interfering with AXL in patient-derived xenograft impaired TGF-β-induced cell invasion. Lastly, pharmacological inhibition of AXL decreased the metastatic burden of mice developing HER2+ breast cancer. Our data identify AXL as a potential co-therapeutic target during the treatment of HER2+ breast cancers to limit metastasis.
2018-05-01 | GSE102369 | GEO
Project description:AXL is activated by its ligand GAS6 and is expressed in triple-negative breast cancer cells. We report that AXL is also detected in HER2+ breast cancer specimens where its expression correlates with poor patients’ survival. Using murine models of HER2+ breast cancer, AXL, but not Gas6, was found essential for metastasis. We determined that AXL is required for intravasation, extravasation and growth at the metastatic site. AXL is expressed in HER2+ cancers displaying EMT signatures and contributes to sustain EMT in murine tumors. Interfering with AXL in patient-derived xenograft impaired TGF-β-induced cell invasion. Lastly, pharmacological inhibition of AXL decreased the metastatic burden of mice developing HER2+ breast cancer. Our data identify AXL as a potential co-therapeutic target during the treatment of HER2+ breast cancers to limit metastasis.
2018-05-01 | GSE102368 | GEO