Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Characterization of the minimal residual disease state reveals distinct evlutionary trajectories of human glioblastoma [single-cell RNA-seq]

ABSTRACT: Recurrence of solid tumors renders patients vulnerable to a distinctly advanced, highly treatment-refractory disease state that has an increased mutational burden and novel oncogenic drivers not detected at initial diagnosis. Improving outcomes for recurrent cancers requires a better understanding of cancer cell populations that expand from the post-therapy, minimal residual disease (MRD) state. We profiled barcoded tumor cell populations through therapy at tumor initiation/engraftment, MRD and recurrence in our therapy-adapted, patient-derived xenograft models of glioblastoma (GBM). Tumors showed distinct patterns of recurrence in which clonal populations exhibited either an a priori, pre-existing fitness advantage, or a priori equipotency fitness acquired through therapy. Characterization of the MRD state by single-cell and bulk RNA sequencing revealed a tumor-intrinsic immunomodulatory signature with strong prognostic significance at the transcriptomic level and in proteomic analysis of cerebrospinal fluid (CSF) collected from GBM patients at all stages of disease. Our results provide insight into the innate and therapy-driven dynamics of human GBM, and the prognostic value of interrogating the MRD state in solid cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE195682 | GEO | 2023/01/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Characterization of the minimal residual disease state reveals distinct evlutionary trajectories of human glioblastoma [Bulk RNA-seq]

Project description:Recurrence of solid tumors renders patients vulnerable to a distinctly advanced, highly treatment-refractory disease state that has an increased mutational burden and novel oncogenic drivers not detected at initial diagnosis. Improving outcomes for recurrent cancers requires a better understanding of cancer cell populations that expand from the post-therapy, minimal residual disease (MRD) state. We profiled barcoded tumor cell populations through therapy at tumor initiation/engraftment, MRD and recurrence in our therapy-adapted, patient-derived xenograft models of glioblastoma (GBM). Tumors showed distinct patterns of recurrence in which clonal populations exhibited either an a priori, pre-existing fitness advantage, or a priori equipotency fitness acquired through therapy. Characterization of the MRD state by single-cell and bulk RNA sequencing revealed a tumor-intrinsic immunomodulatory signature with strong prognostic significance at the transcriptomic level and in proteomic analysis of cerebrospinal fluid (CSF) collected from GBM patients at all stages of disease. Our results provide insight into the innate and therapy-driven dynamics of human GBM, and the prognostic value of interrogating the MRD state in solid cancers.

2023-01-23 | GSE195681 | GEO

Characterization of the minimal residual disease state reveals distinct evlutionary trajectories of human glioblastoma [DNA barcoding]

2023-01-23 | GSE195680 | GEO

Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy

Project description:Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Nonetheless, understanding of GBM is limited to the resectable tumor core lesion while the seeds for recurrence reside in the unresectable tumor edge. In this study, stratification of GBM to core and edge demonstrated clinically relevant surgical sequelae. We establish regionally derived models of GBM edge and core that retain their spatial identity in a cell autonomous manner. Edge cells show a higher capacity for infiltrative growth, while core cells demonstrate greater therapy resistance. Investigation of intercellular signaling between these two cell populations uncovered the paracrine crosstalk from tumor core that provokes malignancy and therapy resistance of edge cells. These phenotypic alterations were initiated by HDAC1 in GBM core cells which subsequently affect edge cells by secreting the soluble form of CD109 protein. Our data reveal the role of intracellular communication between regionally different populations of GBM cells in tumor recurrence.

2020-07-03 | GSE153746 | GEO

An Adipocyte-like Signature in Ovarian Cancer Minimal Residual Disease Identifies Metabolic Vulnerabilities of Tumor Initiating Cells

Project description:Recurrence and metastasis are the main causes of death for cancer patients. Relapse can also occur when complete response is achieved, due to the Minimal Residual Disease (MRD) cells that survive treatment. Here we show that the knowledge gap in solid tumors MRD biology can be reduced studying ovarian cancer and we provide the first molecular characterization of MRD. Transcriptomics analysis of 120 tumor biopsies from 17 patients with different response to treatment revealed that the MRD cells have a very specific adipocyte-like signature. These cells also upregulate fatty acid oxidation (FAO), displaying a vulnerability that can be targeted therapeutically. These findings identify FAO as an attractive target to eradicate MRD in ovarian cancer and make a compelling case for the use of FAO inhibitors in neo-adjuvant settings.

2021-05-05 | GSE162714 | GEO

Gene expression profiles in resistant acute lymphoblastic leukemia

Project description:Treatment resistance as indicated by the presence of high levels of minimal residual disease (MRD) after induction therapy and induction consolidation is associated with a poor prognosis in childhood acute lymphoblastic leukemia (ALL). We hypothesized that treatment resistance is an intrinsic feature of ALL cells, which is reflected in the gene expression pattern, and that resistance to chemotherapy can be predicted prior to treatment. To test these hypotheses, gene expression signatures of ALL samples with a high MRD load (MRD-HR) were compared to those of samples without measurable MRD (MRD-SR) during treatment. We identified 54 genes that clearly distinguished resistant from sensitive ALL samples. Genes low expressed in resistant samples were predominantly associated with cell cycle progression and apoptosis, suggesting that impaired cell proliferation and apoptosis are involved in treatment resistance. Prediction analysis using randomly selected samples as a training set and the remaining samples as a test set revealed an accuracy of 84%. We conclude that resistance to chemotherapy seems at least in part to be an intrinsic feature of ALL cells. As treatment response could be predicted with a high accuracy, gene expression profiling could become a clinically relevant tool for treatment stratification in the early course of childhood ALL. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Keywords: disease_state_design Using regression correlation

2006-01-18 | E-GEOD-4057 | biostudies-arrayexpress

Environmental-mediated vincristine drug resistance of human precursor B-acute lymphoblastic leukemia (pre-B ALL)

Project description:First-line treatment for pre-B acute lymphoblastic leukemia (pre-B ALL) typically encompasses a period of so-called induction therapy in which the patient is treated for 28 days with chemotherapy to induce a remission. A bone marrow sample is subsequently taken to determine the number of remaining leukemia cells, which are called minimal residual disease (MDR). MRD is a key prognostic factor, with higher MRD levels predicting worse outcome for patients. Induction therapy usually is able to drastically reduce the number of leukemic cells but chemoresistance, as first detected by higher MRD levels, remains a major clinical problem. MRD persists not only by leukemia cell-intrinsic mechanisms such as clonal selection and genetic changes, but also through protective interactions of the leukemia cells with the surrounding supporting stroma. This mechanism of drug resistance has been named environment-mediated drug resistance (EMDR) and is a general route through which MRD cells, regardless of underlying genetics of the leukemia cells, can persist after chemotherapy. The EMDR component contributing to the persistence of MRD leukemia cells can be studied in tissue culture models by treating leukemia cells with a non-lethal drug dose in the presence of stromal cell protection. Here we analysed the transcriptome of a PDX-derived human pre-B ALL cell line co-cultured with OP9 stromal cells as they developed drug insensitivity against the chemotherapeutic drug vincristine.

2023-02-28 | GSE176366 | GEO

Metabolic memory underlying minimal residual disease in breast cancer

Project description:<p>Tumor relapse from treatment-resistant cells (minimal residual disease, MRD) underlies most breast cancer related deaths. Yet, the molecular characteristics defining their malignancy have largely remained elusive. Here we integrated multi-omics data from a tractable organoid system with a metabolic modelling approach to uncover the metabolic and regulatory idiosyncrasies of the MRD. We find that the resistant cells, despite their non-proliferative phenotype and the absence of oncogenic signaling, feature increased glycolysis and activity of certain urea cycle enzymes reminiscent of the tumor. This metabolic distinctiveness was also evident in a mouse model and in transcriptomic data from patients following neo-adjuvant therapy. We further identified a marked similarity in DNA methylation profiles between tumor and residual cells. Taken together, our data reveal a metabolic and epigenetic memory of the treatment-resistant cells. We further demonstrate that the memorized elevated glycolysis in MRD is crucial for their survival and can be targeted using a small molecule inhibitor without impacting normal cells. The metabolic aberrances of MRD thus offer new therapeutic opportunities for post-treatment care to prevent breast tumor recurrence.</p>

2021-09-14 | MTBLS1507 | MetaboLights

Anti-Warburg effect elicited by mitochondrial biogenesis drives differentiation of glioblastoma cells into astroglial cells

Project description:Glioblastoma (GBM) is among the most aggressive of human cancers. Although differentiation therapy has been proposed to be potential approach to treat GBM, the mechanisms of induced differentiation remain poorly defined. Here, we established an induced differentiation model of GBM using cAMP activators, which specifically directed GBM into astroglia. We want to use transcriptomic and proteomic analyses to uncover the central regulators of induced differentiation in solid tumor.

2017-01-17 | PXD005334 | Pride

KAT5 activity regulates quiescent-like states in human gliomas [crispr screen]

Project description:In solid tumors, quiescent/G0 cell populations likely play important roles in maintaining cellular heterogeneity and promoting recurrence after stand of care. However, little is known about the mechanisms of tumor cell G0 ingress and egress. To discover regulators of G0-like states for glioblastoma (GBM), we performed a genome-wide CRISPR-Cas9 screen in patient-derived GBM stem-like cells (GSCs) for genes that when inhibited trap cells in G0-like states. We identify the protein acetyltransferase KAT5 as a key regulator of G0 and cell cycle dynamics in GSCs and GSC-derived tumors. In primary gliomas, KAT5low cells display quiescent properties, while overall KAT5 activity increases as tumors become more aggressive. Further, we find that KAT5 activity suppresses the emergence of non-dividing subpopulations with oligodendrocyte progenitor and radial glial cell characteristics both in vitro and in a GSC tumor model. These results reveal that KAT5 activity regulates transitions between non-dividing, neurodevelopmental, and proliferative states in GBM tumors.

2023-12-01 | GSE198523 | GEO

KAT5 activity regulates quiescent-like states in human gliomas [scRNA-seq]

2023-12-01 | GSE198522 | GEO