Profiling the transcriptomic changes in DTC upon germline ablation
Ontology highlight
ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE213802 | GEO | 2024/06/25
REPOSITORIES: GEO
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Project description:The presence of disseminated tumour cells (DTCs) in bone marrow predicts poorer metastasis-free survival of breast cancer patients with localized disease, and their eradication improves long-term prognosis. DTCs persist in distant tissues despite administration of adjuvant chemotherapy, ostensibly because the majority of DTCs are quiescent. Here, we provide evidence that the microenvironment of DTCs protects them from chemotherapy independent of cell cycle status. We show that chemoresistant DTCs associate with the perivascular niche (PVN) of distant tissues, and that they are protected from therapies by vascular endothelium. Inhibiting key integrin-mediated interactions between DTCs and the PVN, driven partly by endothelial-derived von Willebrand Factor, sensitizes DTCs to chemotherapy and prevents bone metastasis. Importantly, chemosensitization is achieved without inducing DTC proliferation, or exacerbating chemotherapy-induced toxicities. These results suggest that prefacing adjuvant therapy with integrin inhibitors is a viable clinical strategy to eradicate DTCs and prevent metastasis.
2019-04-23 | GSE119153 | 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:The period between “successful” treatment of localized breast cancer and the onset of distant metastasis can last many years, representing an unexploited window to eradicate disseminated disease and prevent metastases. We find that the source of recurrence – disseminated tumor cells (DTCs) – evade endogenous immunity directed against tumor neoantigens. Although DTCs downregulate major histocompatibility complex I, this does not preclude recognition by conventional T cells. Instead, the scarcity of interactions between two relatively rare populations – DTCs and endogenous antigen-specific T cells – underlies DTC persistence. This scarcity is overcome by any one of three immunotherapies that increase the number of tumor-specific T cells: T cell-based vaccination, or adoptive transfer of T cell receptor- or chimeric antigen receptor- T cells. Each approach achieves robust DTC elimination, motivating discovery of MHC-restricted and -unrestricted DTC antigens that can be targeted with T cell-based immunotherapies to eliminate the reservoir of metastasis-initiating cells in patients.
2024-01-02 | GSE248295 | 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.
2012-11-19 | GSE27574 | GEO
Project description:Profiling the transcriptomic changes in DTC upon germline ablation
| PRJNA882466 | ENA
Project description:Single-cell assessment of bone marrow metastases is essential to decipher the entire spectrum of tumor heterogeneity in solid cancers with bone marrow involvement. We used multi-epitope-ligand cartography (MELC) to spatially profile 20 biomarkers in 35,000 disseminated tumor cells (DTCs), hematopoietic and mesenchymal cells from eight neuroblastoma bone marrow metastases. We developed DeepFLEX, a single-cell image analysis pipeline for MELC data that combines deep learning-based cell and nucleus segmentation and overcomes frequent challenges of multiplex imaging methods. Comparisons of cell type proportions between samples indicated that microenvironmental changes in the bone marrow are associated with tumor cell infiltration and therapy response. Hierarchical clustering of DTCs revealed multiple phenotypes with highly diverse expression of markers such as FAIM2, which we propose as a complementary marker to capture DTC heterogeneity in neuroblastoma. This single-cell atlas is an important step towards a deeper understanding of DTCs and their interactions with the bone marrow niche.
2021-09-07 | GSE172184 | GEO
Project description:Cancer relapse occurs even after curative treatment, suggesting the existence of undetectable cancer cell subpopulations and their drug-tolerant potential. We found that the number of drug-tolerant colonies (DTCs) was significantly suppressed by an RNA polymerase II (RNAPII) inhibitor, alpha-amanitin (alpha-AMA). To identify potential molecular target of alpha-AMA, we performed transcriptional profiling by Agilent-028004 SurePrint G3 Human GE 8x60K Microarray using untreated colonies and DTCs derived from MCF7. Among the top 2.5% of specifically induced genes in DTCs, we focused on TAF15 gene because its gene product binds RNAPII. A subsequent colony formation assay revealed that TAF15 knockdown suppressed the emergence of both DTCs and untreated colonies, suggesting that TAF15 is a crucial target of alpha-AMA in the context of DTC suppression. Total RNA was extracted from two biological replicates of bulk untreated MCF7 colonies and MCF7 DTCs emerged in the presence of 0.8 µM CIS. For identification of the TAF15 gene, gene ontology analysis was performed using Database for Annotation, Visualization and Integrated Discovery (DAVID) software tools (http://david.abcc.ncifcrf.gov/).
2015-01-30 | E-GEOD-65419 | biostudies-arrayexpress
Project description:Summary: Piwi-interacting RNAs (piRNAs) are important for repressing transposable elements (TEs) and modulating gene expression in germ cells, thereby maintaining genome stability and germ cell function. Here, we show that the canonical piRNA clusters are more active in GSCs (germline stem cells) and their early progeny than late germ cells, and identify new piRNA clusters using deep RNA sequencing. We show that GSCs have higher piRNA levels and lower TE levels than niche cells. Furthermore, many mRNA 3’UTR also exhibit the production of sense, antisense or dual-stranded piRNA. Finally, we show that there are extensive differences in alternative promoter usage and splicing which are likely to modulate gene function in GSCs and niche cells. Overall, this study serves as a major resource for the investigation of piRNA and TE dynamics in GSCs and niche cells.
2019-10-15 | GSE119862 | GEO
Project description:Dissemination of cancer stem cells (CSCs) serves as the basis of metastasis. Recently, we demonstrated that circulating prostate cancer (PCa) targets the hematopoietic stem cell (HSCs) ‘niche’ in marrow during dissemination. Once in the niche, disseminated tumor cells (DTCs) may remain dormant for extended periods. As the major function of the HSC niche is to maintain stem cell functions, we hypothesized that the niche regulates CSC activities of DTCs. We show that DTCs recovered from marrow were significantly enriched for a CSC phenotype. Critically, the conversion of DTCs to CSCs is regulated by niche. The data demonstrate that the niche plays a significant role in maintaining tumor-initiating PCa in marrow and suggests a functional relationship between CSCs and dormancy. Understanding how the marrow niche regulates the conversion of DTCs to CSCs is critical for the development of therapeutics specifically targeting skeletal bone metastasis and dormancy. We used microarrays to determine the global changes in gene expression underlying the significant roles of the marrow niche in activating cancer stem-like cell programs of prostate caner.
2016-01-30 | GSE77379 | GEO
Project description:Cancer relapse occurs even after curative treatment, suggesting the existence of undetectable cancer cell subpopulations and their drug-tolerant potential. We found that the number of drug-tolerant colonies (DTCs) was significantly suppressed by an RNA polymerase II (RNAPII) inhibitor, alpha-amanitin (alpha-AMA). To identify potential molecular target of alpha-AMA, we performed transcriptional profiling by Agilent-028004 SurePrint G3 Human GE 8x60K Microarray using untreated colonies and DTCs derived from MCF7. Among the top 2.5% of specifically induced genes in DTCs, we focused on TAF15 gene because its gene product binds RNAPII. A subsequent colony formation assay revealed that TAF15 knockdown suppressed the emergence of both DTCs and untreated colonies, suggesting that TAF15 is a crucial target of alpha-AMA in the context of DTC suppression.
2015-01-30 | GSE65419 | GEO