Browse
Submit Data
Databases
API
Help

Dataset Information

8 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cellular and Molecular Changes of Brain Metastases-Associated Myeloid Cells during Disease Progression and Therapeutic Response.

ABSTRACT: Brain-resident microglia and bone marrow-derived macrophages represent the most abundant non-cancerous cells in the brain tumor microenvironment with critical functions in disease progression and therapeutic response. To date little is known about genetic programs that drive disease-associated phenotypes of microglia and macrophages in brain metastases. Here we used cytometric and transcriptomic analyses to define cellular and molecular changes of the myeloid compartment at distinct stages of brain metastasis and in response to radiotherapy. We demonstrate that genetic programming of tumor education in myeloid cells occurs early during metastatic onset and remains stable throughout tumor progression. Bulk and single cell RNA sequencing revealed distinct gene signatures in brain-resident microglia and blood-borne monocytes/macrophages during brain metastasis and in response to therapeutic intervention. Our data provide a framework for understanding the functional heterogeneity of brain metastasis-associated myeloid cells based on their origin.

SUBMITTER: Schulz M

PROVIDER: S-EPMC7262568 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Cellular and molecular changes of brain metastases-associated myeloid cells during disease progression and therapeutic response

Project description:Brain metastasis (BrM) represents a challenging clinical issue. The most common treatment options are surgery and irradiation. Little is known about the complex cellular and molecular microenvironment of BrM, thus lacking molecular targets to combat this dismal disease. It is known that macrophages from the periphery (monocyte-derived macrophages, MDM) and microglia, the brain-resident macrophages, comprise the most abundant stromal cell types in BrM. However, it is not known if both cell types represent a homogeneous cell population with redundant functions or if there are differences due to their ontologic origin. Besides breast cancer and melanoma, the highest incidence of BrM can be found in lung cancer. To gain deeper insight into the myeloid immune landscape, we here provide a resource for the transcriptional landscape of distinct myeloid immune cells associated with lung-to-brain metastasis. Microglia, MDMs, inflammatory monocytes, and granulocytes were FACS-purified from lung-to-brain metastasis at distinct stages following tumor onset and during BrM progression. To evaluate molecular changes due to application of standard therapy, these 4 cell types were also purified at distinct time points upon whole brain radiotherapy of tumor-bearing mice. Additionally, microglia of irradiated mice without BrM were analyzed. Together, our RNA Seq data provide a framework for the identification of molecular targets of the myeloid immune cell landscape in lung cancer BrMs.

2020-05-13 | GSE137762 | GEO

Cellular and molecular changes of brain metastases-associated myeloid cells during disease progression and therapeutic response

Project description:Cellular and molecular changes of brain metastases-associated myeloid cells during disease progression and therapeutic response

| PRJNA566454 | ENA

Molecular and cellular stratagem of brain metastases associated with melanoma.

Project description:Tumors of the central nervous system are the most prevalent complications of melanoma, especially in the late stage of disease. Melanoma, lung and breast cancer are the leading cause of secondary tumors in the brain, the majority of them having a poor outcome. Brain dissemination is developed in half of stage IV melanomas and these cases can increase up to 75%, having a major impact on the quality of life. This review will focus on recent findings that provide new ways to potentially prevent brain metastases in malignant melanoma. The key of these findings is based on the heterogeneity of the melanoma and of the brain metastases at genetic levels. This new era of technologies provides new tools in understanding the dissemination mechanisms of malignant cells. The cellular and molecular changes, the immune status of the patient and the blood-brain barrier permeability are key regulators of cancer cell dissemination. Understanding these mechanisms can render new hope in preventing brain metastases by focusing on melanoma and new pharmacologic approaches.

| S-EPMC6444343 | biostudies-literature

Behind Brain Metastases Formation: Cellular and Molecular Alterations and Blood-Brain Barrier Disruption.

Project description:Breast cancer (BC) brain metastases is a life-threatening condition to which accounts the poor understanding of BC cells' (BCCs) extravasation into the brain, precluding the development of preventive strategies. Thus, we aimed to unravel the players involved in the interaction between BCCs and blood-brain barrier (BBB) endothelial cells underlying BBB alterations and the transendothelial migration of malignant cells. We used brain microvascular endothelial cells (BMECs) as a BBB in vitro model, under conditions mimicking shear stress to improve in vivo-like BBB features. Mixed cultures were performed by the addition of fluorescently labelled BCCs to distinguish individual cell populations. BCC-BMEC interaction compromised BBB integrity, as revealed by junctional proteins (β-catenin and zonula occludens-1) disruption and caveolae (caveolin-1) increase, reflecting paracellular and transcellular hyperpermeability, respectively. Both BMECs and BCCs presented alterations in the expression pattern of connexin 43, suggesting the involvement of the gap junction protein. Myosin light chain kinase and phosphorylated myosin light chain were upregulated, revealing the involvement of the endothelial cytoskeleton in the extravasation process. β4-Integrin and focal adhesion kinase were colocalised in malignant cells, reflecting molecular interaction. Moreover, BCCs exhibited invadopodia, attesting migratory properties. Collectively, hub players involved in BC brain metastases formation were unveiled, disclosing possible therapeutic targets for metastases prevention.

| S-EPMC8268492 | biostudies-literature

Tracking cellular and molecular changes in a species-specific manner during experimental tumor progression in vivo.

Project description:Hepatoblastoma (HBL) is a pediatric liver cancer with defined molecular alterations driving its progression. Here, we describe an animal model for HBL on the chick chorioallantoic membrane (CAM), which recapitulates relevant features of HBL in patients. Expression of classic tumor-associated proteins such as ?-catenin, EpCAM and CK19 was maintained in acini-like organized tumors on CAM, as was synthesis of AFP, a tumor marker used for monitoring patient response. RNA sequencing revealed an unexpected molecular evolution of HBL cells on the CAM, with significant deregulation of more than 6,000 genes including more than half of all HOX genes. Bioinformatic analysis distinguish between tumor cell-expressed genes and chick genes, thereby shedding new light on the complex interactions taking place during HBL progression. Importantly, human tumor suppressive ribosomal genes were downregulated after implantation, whereas mitochondrial genes encoding for anti-apoptotic peptides were strongly induced in vivo. Meprin-1? expression was increased during evolution of CAM tumors and confirmed by immunohistochemistry. Cisplatin, a commonly used chemotherapeutic agent for HBL, showed significant anti-tumoral effects. Our results broaden the understanding of the molecular adaptation process of human cancer cells to the microenvironment and might help to elaborate novel therapeutic concepts for the treatment of this pediatric liver tumor.

| S-EPMC5882324 | biostudies-literature

Cellular architecture of human brain metastases.

Project description:Brain metastasis (BrM) is the most common form of brain cancer, characterized by neurologic disability and an abysmal prognosis. Unfortunately, our understanding of the biology underlying human BrMs remains rudimentary. Here, we present an integrative analysis of >100,000 malignant and non-malignant cells from 15 human parenchymal BrMs, generated by single-cell transcriptomics, mass cytometry, and complemented with mouse model- and in silico approaches. We interrogated the composition of BrM niches, molecularly defined the blood-tumor interface, and revealed stromal immunosuppressive states enriched with infiltrated T cells and macrophages. Specific single-cell interrogation of metastatic tumor cells provides a framework of 8 functional cell programs that coexist or anticorrelate. Collectively, these programs delineate two functional BrM archetypes, one proliferative and the other inflammatory, that are evidently shaped through tumor-immune interactions. Our resource provides a foundation to understand the molecular basis of BrM in patients with tumor cell-intrinsic and host environmental traits.

| S-EPMC8857062 | biostudies-literature

Gene expression changes associated with progression and response in chronic myeloid leukemia.

Project description:Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease with distinct biological and clinical features. The biologic basis of the stereotypical progression from chronic phase through accelerated phase to blast crisis is poorly understood. We used DNA microarrays to compare gene expression in 91 cases of CML in chronic (42 cases), accelerated (17 cases), and blast phases (32 cases). Three thousand genes were found to be significantly (P < 10(-10)) associated with phase of disease. A comparison of the gene signatures of chronic, accelerated, and blast phases suggest that the progression of chronic phase CML to advanced phase (accelerated and blast crisis) CML is a two-step rather than a three-step process, with new gene expression changes occurring early in accelerated phase before the accumulation of increased numbers of leukemia blast cells. Especially noteworthy and potentially significant in the progression program were the deregulation of the WNT/beta-catenin pathway, the decreased expression of Jun B and Fos, alternative kinase deregulation, such as Arg (Abl2), and an increased expression of PRAME. Studies of CML patients who relapsed after initially successful treatment with imatinib demonstrated a gene expression pattern closely related to advanced phase disease. These studies point to specific gene pathways that might be exploited for both prognostic indicators as well as new targets for therapy.

| S-EPMC1413797 | biostudies-literature

Cellular immune response to cryptic epitopes during therapeutic gene transfer.

Project description:The immune response has been implicated as a critical factor in determining the success or failure of clinical gene therapy trials. Generally, such a response is elicited by the desired transgene product or, in some cases, the delivery system. In the current study, we report the previously uncharacterized finding that a therapeutic cassette currently being used for human investigation displays alternative reading frames (ARFs) that generate unwanted protein products to induce a cytotoxic T lymphocyte (CTL) response. In particular, we tested the hypothesis that antigenic epitopes derived from an ARF in coagulation factor IX (F9) cDNA can induce CTL reactivity, subsequently killing F9-expressing hepatocytes. One peptide (p18) of 3 candidates from an ARF of the F9 transgene induced CD8(+) T cell reactivity in mice expressing the human MHC class I molecule B0702. Subsequently, upon systemic administration of adeno-associated virus (AAV) serotype 2 vectors packaged with the F9 transgene (AAV2/F9), a robust CD8(+) CTL response was elicited against peptide p18. Of particular importance is that the ARF epitope-specific CTLs eliminated AAV2/F9-transduced hepatocytes but not AAV2/F9 codon-optimized (AAV2/F9-opt)-transduced liver cells in which p18 epitope was deleted. These results demonstrate a previously undiscovered mechanism by which CTL responses can be elicited by cryptic epitopes generated from a therapeutic transgene and have significant implications for all gene therapy modalities. Such unforeseen epitope generation warrants careful analysis of transgene sequences for ARFs to reduce the potential for adverse events arising from immune responses during clinical gene therapy protocols.

| S-EPMC2705599 | biostudies-literature

Brain metastases as preventive and therapeutic targets.

Project description:The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. The brain is considered a 'sanctuary site' as the blood-tumour barrier limits the ability of drugs to enter and kill tumour cells. Translational research examining metastasis to the brain needs to be multi-disciplinary, marrying advanced chemistry, blood-brain barrier pharmacokinetics, neurocognitive testing and radiation biology with metastasis biology, to develop and implement new clinical trial designs. Advances in the chemoprevention of brain metastases, the validation of tumour radiation sensitizers and the amelioration of cognitive deficits caused by whole-brain radiation therapy are discussed.

| S-EPMC7351203 | biostudies-literature

Cellular Architecture of Human Brain Metastases

Project description:Here we present an integrative analysis of 15 human parenchymal BrMs as a resource, generated by single-cell transcriptomics, and complemented with two mouse models- and in silico- approaches. We interrogated the composition of BrM niches, molecularly defined the blood-tumor interface, and reveal stromal immunosuppressive states, enriched with infiltrated T cells and macrophages. Specific single-cell interrogation of metastatic tumor cells provides a novel framework of 8 functional cell programs that coexist or anticorrelate. Collectively, these programs delineate two functional BrM archetypes, one proliferative and the other inflammatory, that are evidently shaped through tumor-immune interactions. Our resource provides a foundation to understand the molecular basis of BrM in patients with tumor cell-intrinsic and host environmental- traits.

2021-11-12 | GSE186344 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data