Identification of genes associated with breast cancer micrometastatic disease in bone marrow using a Patient Derived Xenograft mouse model
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE57947 | GEO | 2018/01/12
SECONDARY ACCESSION(S): PRJNA248472
REPOSITORIES: GEO
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Project description:Neuroblastoma is the most common extra-cranial solid tumor in childhood. Presence of disseminated tumor cells (DTCs) in the bone marrow (BM) at diagnosis and at relapse is a common event in stage M neuroblastomas. Although the clinical heterogeneity of disseminated neuroblastomas is frequently associated with genomic diversity, so far, only little information exists about the genomic status of DTCs. This lack of knowledge is mainly due to the varying amount of BM infiltrating tumor cells, which is usually below 30% even at diagnosis thereby hampering systematic analyses. Thus, a valuable chance to analyze metastatic and relapse clones is, so far, completely unexploited. In this study, we show that the enrichment of tumor cells in fresh or DMSO frozen BM samples with a minimum of 0.05% or 0.1% infiltration rate, respectively, by applying magnetic beads technique increased the DTC content to a sufficient level to allow SNP array analyses in 49 out of 69 samples. In addition, we successfully used non-enriched BM samples with ≥30% DTCs including non-stained and immunostained cytospin and BM smear slides for SNP array analyses in 44 cases. We analyzed the genomic profile of DTCs by an ultra-high density SNP array technique with highest performance detecting all segmental chromosomal aberrations, amplified regions, acquired loss of heterozygosity events and minor aberrations affecting single genes or parts thereof.
2014-12-31 | GSE59537 | GEO
Project description:In this study, we assess the effect of zoledronic acid on clearance of disseminated tumour cells (DTCs) from the bone marrow in women undergoing neoadjuvant chemotherapy for breast cancer In this dataset, Primary breast tissue from stage II or III breast cancer patients were included in the analysis. This study allowed the identification of novel gene expression patterns associated with the presence of DTCs BM by IHC and supports the concept of epithelial to mesenchymal transition transition (EMT) of DTCs present in the BM .
2015-12-16 | E-GEOD-71258 | biostudies-arrayexpress
Project description:How disseminated tumor cells (DTCs) engage specific stromal components in distant organs for survival and outgrowth is a critical but poorly understood step of the metastatic cascade. Previous studies have demonstrated the importance of the epithelial-mesenchymal transition (EMT) in promoting the cancer stem cell properties needed for metastasis initiation, while the reverse process of mesenchymal-epithelial transition (MET) is required for metastatic outgrowth. Here we report that this paradoxical requirement for simultaneous induction of both MET and cancer stem cell traits in DTCs is provided by bone vascular niche E-selectin. Using cell surface alkoxyamine-biotinylation and label-free LC-MS/MS, Glg1 was identified as a top candidate Fut3/Fut6-dependent E-selectin ligand. We functionally validated their involvement in the formation of bone metastasis. These findings provide unique insights into the functional role of E-selectin as a component of the vascular niche criticalfor metastatic colonization in bone.
2019-11-13 | PXD012942 | Pride
Project description:The development of efficacious therapies targeting metastatic spread of breast cancer to the brain represents an unmet clinical need. Accordingly, an improved understanding of the molecular underpinnings of central nervous system spread and progression of breast cancer brain metastases (BCBM) is required. In this study, the clinical burden of disease in BCBM was investigated, as well as the role of aldehyde dehydrogenase 1A3 (ALDH1A3) in the metastatic cascade leading to BCBM development. Initial analysis of clinical survival trends for breast cancer and BCBM determined improvement of breast cancer survival rates, however this has failed to positively impact the prognostic milestones of triple-negative breast cancer (TNBC) brain metastases (BM). ALDH1A3 and a representative epithelial-mesenchymal transition (EMT) gene signature (mesenchymal markers CD44, Vimentin) were compared in tumors derived from BM, lung metastases (LM) or bone metastases (BoM) of patients as well as mice post-injection of TNBC cells. Selective elevation of the EMT signature and ALDH1A3 were observed in BM, unlike LM and BoM, especially in the tumor edge. Furthermore, ALDH1A3 was determined to play a role in BCBM establishment via regulation of circulating tumor cell (CTC) adhesion and migration phases in the BCBM cascade. Validation through genetic and pharmacologic inhibition of ALDH1A3 via lentiviral shRNA knockdown and a novel small molecule inhibitor demonstrated selective inhibition of BCBM formation with prolonged survival of tumor-bearing mice. Given the survival benefits via targeting ALDH1A3, it may prove an effective therapeutic strategy for BCBM prevention and/or treatment.
2020-01-01 | GSE138361 | GEO
Project description:Background: Neuroblastoma is the most common extracranial solid tumor in childhood. The vast majority of stage M patients present with disseminated tumor cells (DTCs) in the bone marrow (BM). Although these cells represent a major obstacle in the treatment of neuroblastoma patients, their transcriptomic profile was not intensively analyzed so far. Results: RNA-Seq of stage M primary tumors, enriched BM-derived DTCs and the corresponding non-tumor mononuclear cells (MNCs) revealed that DTCs largely retained the gene expression signature of tumors. However, we identified 322 genes that were differentially expressed (q < 0.001, |log2FC|>2). Particularly genes encoded by mitochondrial DNA were highly up-regulated in DTCs, whereas e.g. genes involved in angiogenesis were down-regulated. Furthermore, 224 genes were highly expressed in DTCs and only slightly, if at all, in MNCs (q < 8x10-75 log2FC > 6). Interestingly, we found that the gene expression profiles of diagnostic DTCs largely resembled those of relapse DTCs with only 113 differentially expressed genes under relaxed cut-offs (q < 0.01, |log2FC| > 0.5). Notably, relapse DTCs showed a positional enrichment of 31 down-regulated genes encoded by chromosome 19, including five tumor suppressor genes (SIRT6, PUMA, STK11, CADM4 and GLTSCR2). Conclusion: This first RNA-Seq analysis of DTCs from neuroblastoma patients revealed their unique expression profile in comparison to the corresponding MNCs and tumor samples, and, interestingly, also expression differences between diagnostic and relapse DTCs preferentially affecting chromosome 19. As these alterations might be associated with treatment failure and disease relapse, they should be considered for further functional studies.
2017-08-21 | GSE94035 | GEO
Project description:Background: Since the high relapse rate is considered to be responsible for the poor survival of stage M neuroblastoma patients, we tested whether the genomic information of bone marrow-derived disseminated tumor cells (DTCs) would help to better understand tumor evolution and to characterize the relapse-seeding clone. Methods: Seven samples from different regions of a primary tumor of a stage M neuroblastoma patient, corresponding DTCs at diagnosis, and DTCs and a metastatic tumor at relapse were analyzed by a high-density SNP array. Relapse-associated chromosomal aberrations found in this case were then validated in DTCs and tumor samples of 154 stage M neuroblastoma patients. Findings: In this case study, unique aberrations were evident in certain tissue/time points aside from a high concordance of genomic aberrations between all analyzed samples. Surprisingly, DTCs at diagnosis, and DTCs and the metastatic tumor at relapse all displayed a terminal deletion in 1q which was not detected in any of the primary tumor samples. In the validation cohort, 1q terminal deletions were found with a higher frequency in DTCs at diagnosis (17.8%) and at relapse (27.5%) compared to primary tumors (11%). 1q deletions were significantly associated with 19q and ATRX deletions. The presence of each individual aberration in the diagnostic DTCs was associated with an increased likelihood of an adverse event and in case of 19q deletion with a decreased overall survival. Moreover, PTPRD deletion and loss of chromosome Y had significantly higher frequencies in the relapse samples compared to the diagnostic samples. Interpretation: These data strongly suggest a branched clonal evolution and a parallel progression of primary and metastatic tumor cells. In addition, the higher frequency of relapse-associated genomic aberrations in the diagnostic DTCs compared to the primary tumors and their effect on the event-free survival rate indicate that analysis of DTCs at diagnosis may provide a higher probability for detecting the relapse-seeding clone compared to the primary tumor. Background: Since the high relapse rate is considered to be responsible for the poor survival of stage M neuroblastoma patients, we tested whether the genomic information of bone marrow-derived disseminated tumor cells (DTCs) would help to better understand tumor evolution and to characterize the relapse-seeding clone. Methods: Seven samples from different regions of a primary tumor of a stage M neuroblastoma patient, corresponding DTCs at diagnosis, and DTCs and a metastatic tumor at relapse were analyzed by a high-density SNP array. Relapse-associated chromosomal aberrations found in this case were then validated in DTCs and tumor samples of 154 stage M neuroblastoma patients. Findings: In this case study, unique aberrations were evident in certain tissue/time points aside from a high concordance of genomic aberrations between all analyzed samples. Surprisingly, DTCs at diagnosis, and DTCs and the metastatic tumor at relapse all displayed a terminal deletion in 1q which was not detected in any of the primary tumor samples. In the validation cohort, 1q terminal deletions were found with a higher frequency in DTCs at diagnosis (17.8%) and at relapse (27.5%) compared to primary tumors (11%). 1q deletions were significantly associated with 19q and ATRX deletions. The presence of each individual aberration in the diagnostic DTCs was associated with an increased likelihood of an adverse event and in case of 19q deletion with a decreased overall survival. Moreover, PTPRD deletion and loss of chromosome Y had significantly higher frequencies in the relapse samples compared to the diagnostic samples. Interpretation: These data strongly suggest a branched clonal evolution and a parallel progression of primary and metastatic tumor cells. In addition, the higher frequency of relapse-associated genomic aberrations in the diagnostic DTCs compared to the primary tumors and their effect on the event-free survival rate indicate that analysis of DTCs at diagnosis may provide a higher probability for detecting the relapse-seeding clone compared to the primary tumor.
2017-08-31 | GSE84291 | GEO
Project description:The aim of this study was to establish a single-cell array comparative genomic hybridization (SCaCGH) method providing in-depth genomic analysis of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs). The robustness and resolution limits of the method were estimated with different cell amounts of the breast cancer cell line SKBR3 using 44k and 244k arrays. Subsequent adjustments of the method were conducted analyzing the copy number profiles of 28 CTCs in combination with four hematopoietic cell (HC) controls from eight metastatic patients and of 24 DTCs, three probable HCs, and five HC controls from seven breast cancer patients and one healthy donor. The frequency of the major genomic gains and losses of the analyzed DTC revealed similarities to primary breast tumor samples with some evident differences. Three of the patients had available profiles for DTC and the corresponding primary tumor. In 2/3 of the examined DTCs, equivalent genomic changes and common aberration breakpoints were disclosed, both to each other and to the corresponding primary tumors. Interestingly, similar copy number changes were found in DTCs taken at time of diagnosis or in DTCs collected at 3-years relapse-free follow up. Residual immunomorphological characterized tumor cells showed balanced profiles with only minor aberrations. Three cells with unclear morphological identification showed either balanced profiles (n=2) or aberrations comparable to the primary tumor and DTC (n=1). SCaCGH may be a powerful tool for molecular characterisation of immunostained and morphological identified CTCs and DTCs to explore the malignant potential, therapeutic targets and tumor heterogeneity of single tumor cells. 24 DTCs, 3 probable HCs, and 5 HCs from 7 early-stage breast cancer patients, 28 CTCs and 4 HCs from 8 metastatic breast cancer patients, and 1 healthy donor were analysed. Comparison with the primary tumor was done in 3 patients. The reference for the patients was DNA from multiple anonymous female donors. This submission does not include the SKBR3 data obtained from the 44k array.
2012-11-19 | E-GEOD-27574 | biostudies-arrayexpress
Project description:Developing animal models representating the cancer biology of advanced prostate cancer patients is challenging but essential for delivering individualized medical therapies. In an effort to develop patient derived xenograft (PDX) models, we took the metastatic site tissue from the rib lesion twice (ie, before and after enzalutamide treatment) over a twelve week period and implanted subcutaneously and under the renal capsule in immuno-deficient mice. To characterize and compare the genome and transcriptome landscapes of patient tumor tissues and the corresponding PDX models, we performed whole exome and transcriptome sequencing for metastatic tumor tissue as well as its derived PDXs. We demonstrated the feasibility of developping PDX models from patient who developed castrate-resistant prostate cancer. Our data suggested PDX models preserve the patient’s genomic and transcriptomic alterations in high fidelity, as illustrated by somatic mutation, copy number variation, gene fusion and gene expression. RNA sequencing of prostate cancer tumor tissue and derived xenograft using Illumina HiSeq 2000.
2015-06-30 | E-GEOD-70380 | biostudies-arrayexpress
Project description:We demonstrate that monocytic and granulocytic subsets of myeloid derived suppressor cells (mMDS, gMDSC) infiltrated in the primary tumor and distant organs with different time kinetics regulate spatiotemporal tumor plasticity. Using co-culture experiments and syngeneic mouse models, we provide evidence that tumor infiltrated mMDSCs facilitate tumor cell dissemination from the primary site by inducing EMT/CSC phenotype. In contrast, pulmonary gMDSC infiltrates support the metastatic growth by reverting EMT/CSC phenotype and in turn promote tumor cell proliferation. Furthermore, lung-derived gMDSCs isolated from tumor bearing animals significantly enhance metastatic growth of already disseminated tumor cells. A “metastatic gene signature” identified in aggressive murine tumors following co-culture with MDSC subsets predicts poor patient survival in majority of human solid tumors suggesting clinical implications of our studies.
2016-05-21 | GSE81701 | GEO
Project description:To determine the effect of tumor-bearing vs. host neutrophilic inflammation on reinforcement of lung neutrophil-specific immunosuppressive function, we performed single-cell RNA sequencing (scRNA-seq) on BM, PB and lung neutrophils isolated from naïve (C57BL/6J), AT3, and AT3-gcsf tumor-bearing mice.
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