Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cell Clustering Promotes a Metabolic Switch that Supports Metastatic Colonization.

ABSTRACT: Cancer metastasis depends on cell survival following loss of extracellular matrix attachment and dissemination through the circulation. The metastatic spread can be enhanced by the clustering of detached cancer cells and increased antioxidant defense. Here, we link these responses by describing how cell clustering limits reactive oxygen species (ROS). Loss of attachment causes mitochondrial perturbations and increased ROS production. The formation of cell clusters induces a hypoxic environment that drives hypoxia-inducible factor 1-alpha (Hif1α)-mediated mitophagy, clearing damaged mitochondria and limiting ROS. However, hypoxia and reduced mitochondrial capacity promote dependence on glycolysis for ATP production that is supported by cytosolic reductive metabolism. Preventing this metabolic adaptation or disruption of cell clusters results in ROS accumulation, cell death, and a reduction of metastatic capacity in vivo. Our results provide a mechanistic explanation for the role of cell clustering in supporting survival during extracellular matrix detachment and metastatic spread and may point to targetable vulnerabilities.

SUBMITTER: Labuschagne CF

PROVIDER: S-EPMC6863392 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Tumor cell metabolic reprogramming and hypoxic immunosuppression: driving carcinogenesis to metastatic colonization.

Project description:A significant factor in the antitumor immune response is the increased metabolic reprogramming of immunological and malignant cells. Increasing data points to the fact that cancer metabolism affects not just cancer signaling, which is essential for maintaining carcinogenesis and survival, but also the expression of immune cells and immune-related factors such as lactate, PGE2, arginine, IDO, which regulate the antitumor immune signaling mechanism. In reality, this energetic interaction between the immune system and the tumor results in metabolic competition in the tumor ecosystem, limiting the amount of nutrients available and causing microenvironmental acidosis, which impairs the ability of immune cells to operate. More intriguingly, different types of immune cells use metabolic reprogramming to keep the body and self in a state of homeostasis. The process of immune cell proliferation, differentiation, and performance of effector functions, which is crucial to the immune response, are currently being linked to metabolic reprogramming. Here, we cover the regulation of the antitumor immune response by metabolic reprogramming in cancer cells and immune cells as well as potential strategies for metabolic pathway targeting in the context of anticancer immunotherapy. We also discuss prospective immunotherapy-metabolic intervention combinations that might be utilized to maximize the effectiveness of current immunotherapy regimes.

| S-EPMC10824957 | biostudies-literature

Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization.

Project description:During metastatic colonization, tumor cells must establish a favorable microenvironment or niche that will sustain their growth. However, both the temporal and molecular details of this process remain poorly understood. Here, we found that metastatic initiating cells (MICs) exhibit a high capacity for lung fibroblast activation as a result of Thrombospondin 2 (THBS2) expression. Importantly, inhibiting the mesenchymal phenotype of MICs by blocking the epithelial-to-mesenchymal transition (EMT)-associated kinase AXL reduces THBS2 secretion, niche-activating ability, and, consequently, metastatic competence. Subsequently, disseminated metastatic cells revert to an AXL-negative, more epithelial phenotype to proliferate and decrease the phosphorylation levels of TGF-β-dependent SMAD2-3 in favor of BMP/SMAD1-5 signaling. Remarkably, newly activated fibroblasts promote this transition. In summary, our data reveal a crosstalk between cancer cells and their microenvironment whereby the EMT status initially triggers and then is regulated by niche activation during metastatic colonization.

| S-EPMC4695340 | biostudies-literature

Active Remodeling of Capillary Endothelium via Cancer Cell-Derived MMP9 Promotes Metastatic Brain Colonization.

Project description:Crossing the blood-brain barrier is a crucial, rate-limiting step of brain metastasis. Understanding of the mechanisms of cancer cell extravasation from brain microcapillaries is limited as the underlying cellular and molecular processes cannot be adequately investigated using in vitro models and endpoint in vivo experiments. Using ultrastructural and functional imaging, we demonstrate that dynamic changes of activated brain microcapillaries promote the mandatory first steps of brain colonization. Successful extravasation of arrested cancer cells occurred when adjacent capillary endothelial cells (EC) entered into a distinct remodeling process. After extravasation, capillary loops were formed, which was characteristic of aggressive metastatic growth. Upon cancer cell arrest in brain microcapillaries, matrix-metalloprotease 9 (MMP9) was expressed. Inhibition of MMP2/9 and genetic perturbation of MMP9 in cancer cells, but not the host, reduced EC projections, extravasation, and brain metastasis outgrowth. These findings establish an active role of ECs in the process of cancer cell extravasation, facilitated by cross-talk between the two cell types. This extends our understanding of how host cells can contribute to brain metastasis formation and how to prevent it.SignificanceTracking single extravasating cancer cells using multimodal correlative microscopy uncovers a brain seeding mechanism involving endothelial remodeling driven by cancer cell-derived MMP9, which might enable the development of approaches to prevent brain metastasis. See related commentary by McCarty, p. 1167.

| S-EPMC7614438 | biostudies-literature

Mesenchymal cancer cell-stromal crosstalk promotes niche activation, epithelial reversion and metastatic colonization

Project description:The experiment was design to address the intrinsic differences between metastatic cancer stem cells in the primary tumour and during metastatic colonization in the mouse mammary gland tumour model MMTV-pyMT. Total RNA was prepared from the indicated cancer cells freshly isolated, stained and FACS sorted either from primary tumours or from lungs upon intravenous injection of cancer cells.

2015-11-21 | E-GEOD-63558 | biostudies-arrayexpress

Peroxynitrite supports a metabolic reprogramming in merlin-deficient Schwann cells and promotes cell survival.

Project description:Neurofibromatosis type 2 (NF2) is an autosomal-dominant disorder characterized by the development of bilateral vestibular schwannomas. The NF2 gene encodes the tumor suppressor merlin, and loss of merlin activity promotes tumorigenesis and causes NF2. Cellular redox signaling has been implicated in different stages of tumor development. Among reactive nitrogen species, peroxynitrite is the most powerful oxidant produced by cells. We recently showed that peroxynitrite-mediated tyrosine nitration down-regulates mitochondrial metabolism in tumor cells. However, whether peroxynitrite supports a metabolic shift that could be exploited for therapeutic development is unknown. Here, we show that vestibular schwannomas from NF2 patients and human, merlin-deficient (MD) Schwann cells have high levels of endogenous tyrosine nitration, indicating production of peroxynitrite. Furthermore, scavenging or inhibiting peroxynitrite formation significantly and selectively decreased survival of human and mouse MD-Schwann cells. Using multiple complementary methods, we also found that merlin deficiency leads to a reprogramming of energy metabolism characterized by a peroxynitrite-dependent decrease of oxidative phosphorylation and increased glycolysis and glutaminolysis. In MD-Schwann cells, scavenging of peroxynitrite increased mitochondrial oxygen consumption and membrane potential, mediated by the up-regulation of the levels and activity of mitochondrial complex IV. This increase in mitochondrial activity correlated with a decrease in the glycolytic rate and glutamine dependence. This is the first demonstration of a peroxynitrite-dependent reprogramming of energy metabolism in tumor cells. Oxidized proteins constitute a novel target for therapeutic development not only for the treatment of NF2 schwannomas but also other tumors in which peroxynitrite plays a regulatory role.

| S-EPMC6663865 | biostudies-literature

Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization.

Project description:Although the role of miR-200s in regulating E-cadherin expression and epithelial-to-mesenchymal transition is well established, their influence on metastatic colonization remains controversial. Here we have used clinical and experimental models of breast cancer metastasis to discover a pro-metastatic role of miR-200s that goes beyond their regulation of E-cadherin and epithelial phenotype. Overexpression of miR-200s is associated with increased risk of metastasis in breast cancer and promotes metastatic colonization in mouse models, phenotypes that cannot be recapitulated by E-cadherin expression alone. Genomic and proteomic analyses revealed global shifts in gene expression upon miR-200 overexpression toward that of highly metastatic cells. miR-200s promote metastatic colonization partly through direct targeting of Sec23a, which mediates secretion of metastasis-suppressive proteins, including Igfbp4 and Tinagl1, as validated by functional and clinical correlation studies. Overall, these findings suggest a pleiotropic role of miR-200s in promoting metastatic colonization by influencing E-cadherin-dependent epithelial traits and Sec23a-mediated tumor cell secretome.

| S-EPMC3169707 | biostudies-literature

Myeloid heme oxygenase-1 promotes metastatic tumor colonization in mice.

Project description:Heme oxygenase-1 (HO-1) is a heme degradation enzyme with antioxidant and immune-modulatory functions. HO-1 promotes tumorigenesis by enhancing tumor cell proliferation and invasion. Whether HO-1 has an effect on cancer progression through stromal compartments is less clear. Here we show that the growth of tumor engrafted subcutaneously in syngeneic mice was not affected by host HO-1 expression. However, lung metastasis arisen from subcutaneous tumor or circulating tumor cells was significantly reduced in HO-1(+/-) mice comparing to wild type (WT) mice. The reduced lung metastasis was also observed in B6 mice bearing HO-1(+/-) bone marrow as comparing to WT chimeras, indicating that HO-1 expression in hematopoietic cells impacts tumor colonization at the metastatic site. Further experiments demonstrated that the numbers of myeloid cells recruited to pulmonary premetastatic niches and metastatic loci were significantly lower in HO-1(+/-) mice than in WT mice. Likewise, the extents of tumor cell extravasation and colonization at the metastatic loci in the early phase of metastasis were significantly lower in HO-1(+/-) mice. Mechanistic studies revealed that HO-1 impacted chemoattractant-induced myeloid cell migration by modulating p38 kinase signaling. Moreover, myeloid HO-1-induced expressions of vascular endothelial growth factor and interleukin-10 promoted tumor cell transendothelial migration and STAT3 activation in vitro. These data support a pathological role of myeloid HO-1 in metastasis and suggest a possibility of targeting myeloid HO-1 for cancer treatment.

| S-EPMC4376439 | biostudies-literature

The Drosophila estrogen-related receptor directs a metabolic switch that supports developmental growth.

Project description:Metabolism must be coordinated with development to provide the appropriate energetic needs for each stage in the life cycle. Little is known, however, about how this temporal control is achieved. Here, we show that the Drosophila ortholog of the estrogen-related receptor (ERR) family of nuclear receptors directs a critical metabolic transition during development. dERR mutants die as larvae with low ATP levels and elevated levels of circulating sugars. The expression of active dERR protein in mid-embryogenesis triggers a coordinate switch in gene expression that drives a metabolic program normally associated with proliferating cells, supporting the dramatic growth that occurs during larval development. This study shows that dERR plays a central role in carbohydrate metabolism, demonstrates that a proliferative metabolic program is used in normal developmental growth, and provides a molecular context to understand the close association between mammalian ERR family members and cancer.

| S-EPMC3072597 | biostudies-literature

Amplification of RANK- and c-Met-mediated signaling promotes metastatic colonization

Project description:We found that RANKL, expressed by cancer cells or derived from exogenous sources, consistently induced human prostate, breast, kidney, lung and liver cancer cells to colonize or metastasize to bone in an animal model of cancer bone metastasis. RANK-mediated signaling established a premetastatic niche through a forward feedback loop by inducing RANKL and c-Met expression and downstream signaling via upregulation of master regulator transcription factors regulating EMT (Twist1, Slug, Zeb1, Zeb2), stem cells (Sox2, Myc, Oct3/4 and Nanog), neuroendocrine cells (Sox 9, HIF-1α and FoxA2) and osteomimicry (c-Myc/Max, Sox2, Sox9, HIF1α and Runx2). Abrogating RANK or its downstream signaling network, c-Myc/Max or c-Met, abolished PCa skeletal metastasis in mice. We observed that a small number of RANKL-expressing PCa cells can initiate bone and soft tissue metastases by recruiting non-tumorigenic or bystander PCa or host cells from the circulation or at metastatic sites to co-colonize bone. The recruited bystander PCa cells assume the phenotypes of RANKL-expressing PCa cells by expressing increased c-Met, phosphorylated c-Met and RANKL. RANKL expression at a single cell level in primary PCa tissues predicted disease-specific survival, reflecting the significant role of RANKL-RANK signaling in the development of lethal bone metastasis. Global gene expression analysis perturbed by RANKL in LNRANKL compared to LNNeo cells.

2014-02-06 | E-GEOD-48432 | biostudies-arrayexpress

Flura-seq identifies organ-specific metabolic adaptations during early metastatic colonization.

Project description:Metastasis-initiating cells dynamically adapt to the distinct microenvironments of different organs, but these early adaptations are poorly understood due to the limited sensitivity of in situ transcriptomics. We developed fluorouracil-labeled RNA sequencing (Flura-seq) for in situ analysis with high sensitivity. Flura-seq utilizes cytosine deaminase (CD) to convert fluorocytosine to fluorouracil, metabolically labeling nascent RNA in rare cell populations in situ for purification and sequencing. Flura-seq revealed hundreds of unique, dynamic organ-specific gene signatures depending on the microenvironment in mouse xenograft breast cancer micrometastases. Specifically, the mitochondrial electron transport Complex I, oxidative stress and counteracting antioxidant programs were induced in pulmonary micrometastases, compared to mammary tumors or brain micrometastases. We confirmed lung metastasis-specific increase in oxidative stress and upregulation of antioxidants in clinical samples, thus validating Flura-seq's utility in identifying clinically actionable microenvironmental adaptations in early metastasis. The sensitivity, robustness and economy of Flura-seq are broadly applicable beyond cancer research.

| S-EPMC6440742 | biostudies-literature

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