Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Learning therapeutic lessons from metastasis suppressor proteins.

ABSTRACT: Metastasis suppressor proteins regulate multiple steps in the metastatic cascade, including cancer cell invasion, survival in the vascular and lymphatic circulation, and colonization of distant organ sites. Understanding the biology of metastasis suppressors provides valuable mechanistic insights that may translate to therapeutic opportunities. Several reports have explored novel strategies for restoring metastasis suppressor function, including gene transfer, induction of previously suppressed gene expression and exogenous administration of gene product. Pathways activated downstream of metastasis suppressor loss can also be targeted. Although none of these strategies are yet in routine clinical use, several are being tested preclinically and in clinical trials.

SUBMITTER: Smith SC

PROVIDER: S-EPMC2881216 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Learning therapeutic lessons from metastasis suppressor proteins.

Smith Steven Christopher SC Theodorescu Dan D

Nature reviews. Cancer 20090226 4

Metastasis suppressor proteins regulate multiple steps in the metastatic cascade, including cancer cell invasion, survival in the vascular and lymphatic circulation, and colonization of distant organ sites. Understanding the biology of metastasis suppressors provides valuable mechanistic insights that may translate to therapeutic opportunities. Several reports have explored novel strategies for restoring metastasis suppressor function, including gene transfer, induction of previously suppressed ...[more]

PMID: 19242414

Similar Datasets

Deep Learning Reveals Cancer Metastasis and Therapeutic Antibody Targeting in the Entire Body.

Project description:Reliable detection of disseminated tumor cells and of the biodistribution of tumor-targeting therapeutic antibodies within the entire body has long been needed to better understand and treat cancer metastasis. Here, we developed an integrated pipeline for automated quantification of cancer metastases and therapeutic antibody targeting, named DeepMACT. First, we enhanced the fluorescent signal of cancer cells more than 100-fold by applying the vDISCO method to image metastasis in transparent mice. Second, we developed deep learning algorithms for automated quantification of metastases with an accuracy matching human expert manual annotation. Deep learning-based quantification in 5 different metastatic cancer models including breast, lung, and pancreatic cancer with distinct organotropisms allowed us to systematically analyze features such as size, shape, spatial distribution, and the degree to which metastases are targeted by a therapeutic monoclonal antibody in entire mice. DeepMACT can thus considerably improve the discovery of effective antibody-based therapeutics at the pre-clinical stage. VIDEO ABSTRACT.

| S-EPMC7591821 | biostudies-literature

A Targeted Proteomic Approach for Heat Shock Proteins Reveals DNAJB4 as a Suppressor for Melanoma Metastasis.

Project description:Heat shock proteins are molecular chaperones that are involved in protein folding. In this study, we developed a targeted proteomic method, relying on LC-MS/MS in the parallel-reaction monitoring (PRM) mode, for assessing quantitatively the human heat shock proteome. The method facilitated the coverage of approximately 70% of the human heat shock proteome and displayed much better throughput and sensitivity than the shotgun proteomic approach. We also applied the PRM method for assessing the differential expression of heat shock proteins in three matched primary/metastatic pairs of melanoma cell lines. We were able to quantify ∼45 heat shock proteins in each pair of cell lines, and the quantification results revealed that DNAJB4 is down-regulated in the three lines of metastatic melanoma cells relative to the corresponding primary melanoma cells. Interrogation of The Cancer Genome Atlas data showed that lower levels of DNAJB4 expression conferred poorer prognosis in melanoma patients. Moreover, we found that DNAJB4 suppresses the invasion of cultured melanoma cells through diminished expression and activities of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9). Together, we established, for the first time, a high-throughput targeted proteomics method for profiling quantitatively the human heat shock proteome and discovered DNAJB4 as a suppressor for melanoma metastasis.

| S-EPMC6154490 | biostudies-literature

PHOX2B is a suppressor of neuroblastoma metastasis.

Project description:Paired like homeobox 2B (PHOX2B) is a minimal residual disease (MRD) marker of neuroblastoma. The presence of MRD, also referred to as micro-metastases, is a powerful marker of poor prognosis in neuroblastoma. Lung metastasis is considered a terminal event in neuroblastoma. Lung micro-metastatic neuroblastoma (MicroNB) cells show high expression levels of PHOX2B and possess a less malignant and metastatic phenotype than lung macro metastatic neuroblastoma (MacroNB) cells, which hardly express PHOX2B. In vitro assays showed that PHOX2B knockdown in MicroNB cells did not affect cell viability; however it decreased the migratory capacity of the MicroNB-shPHOX2B cells. An orthotopic inoculation of MicroNB-shPHOX2B cells into the adrenal gland of nude mice resulted in significantly larger primary tumors and a heavier micro-metastatic load in the lungs and bone-marrow, than when control cells were inoculated. PHOX2B expression was found to be regulated by methylation. The PHOX2B promoter in MacroNB cells is significantly more methylated than in MicroNB cells. Demethylation assays using 5-azacytidine demonstrated that methylation can indeed inhibit PHOX2B transcription in MacroNB cells. These pre-clinical data strongly suggest that PHOX2B functions as a suppressor of neuroblastoma progression.

| S-EPMC4891146 | biostudies-literature

Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7.

Project description:Metastasis is the main cause of death in cancer patients. TGF-β is pro-metastatic for malignant cancer cells. Here we report a loss-of-function screen in mice with metastasis as readout and identify OTUD1 as a metastasis-repressing factor. OTUD1-silenced cancer cells show mesenchymal and stem-cell-like characteristics. Further investigation reveals that OTUD1 directly deubiquitinates the TGF-β pathway inhibitor SMAD7 and prevents its degradation. Moreover, OTUD1 cleaves Lysine 33-linked poly-ubiquitin chains of SMAD7 Lysine 220, which exposes the SMAD7 PY motif, enabling SMURF2 binding and subsequent TβRI turnover at the cell surface. Importantly, OTUD1 is lost in multiple types of human cancers and loss of OTUD1 increases metastasis in intracardial xenograft and orthotopic transplantation models, and correlates with poor prognosis among breast cancer patients. High levels of OTUD1 inhibit cancer stemness and shut off metastasis. Thus, OTUD1 represses breast cancer metastasis by mitigating TGF-β-induced pro-oncogenic responses via deubiquitination of SMAD7.

| S-EPMC5727433 | biostudies-literature

Lessons from immunology: IL4R directly promotes mammary tumor metastasis.

Project description:Interleukin-4 (IL4), a Th2 cytokine, signals through IL4 receptors (IL4Rs) to regulate increased lymphocyte proliferation and survival. We have recently discovered that IL4 also promotes these phenotypes in mammary cancer cells expressing IL4Rs to enhance their metastatic ability. Targeting IL4/IL4R signaling on cancer cells themselves may limit metastatic disease.

| S-EPMC4292563 | biostudies-other

Therapeutic vaccines in HBV: lessons from HCV.

Project description:Currently, millions of people infected with hepatitis B virus (HBV) are committed to decades of treatment with anti-viral therapy to control viral replication. However, new tools for immunotherapy that include both viral vectors and molecular checkpoint inhibitors are now available. This has led to a resurgence of interest in new strategies to develop immunotherapeutic strategies with the aim of inducing HBeAg seroconversion--an end-point that has been associated with a decrease in the rates of disease progression. Ultimately, a true cure will involve the elimination of covalently closed circular DNA which presents a greater challenge for immunotherapy. In this manuscript, I describe the development of immunotherapeutic strategies for HBV that are approaching or currently in clinical studies, and draw on observations of T cell function in natural infection supported by recent animal studies that may lead to additional rational vaccine strategies using checkpoint inhibitors. I also draw on our recent experience in developing potent vaccines for HCV prophylaxis based on simian adenoviral and MVA vectors used in prime-boost strategies in both healthy volunteers and HCV infected patients. I have shown that the induction of T cell immune responses is markedly attenuated when administered to people with persistent HCV viremia. These studies and recently published animal studies using the woodchuck model suggest that potent vaccines based on DNA or adenoviral vectored vaccination represent a rational way forward. However, combining these with drugs to suppress viral replication, alongside checkpoint inhibitors may be required to induce long-term immune control.

| S-EPMC4305103 | biostudies-literature

Auranofin is a potent suppressor of osteosarcoma metastasis.

Project description:Osteosarcoma (OS) accounts for 56% of malignant bone cancers in children and adolescents. Patients with localized disease rarely develop metastasis; however, pulmonary metastasis occurs in approximately 50% of patients and leads to a 5-year survival rate of only 10-20%. Therefore, identifying the genes and pathways involved in metastasis, as new therapeutic targets, is crucial to improve long-term survival of OS patients. Novel markers that define metastatic OS were identified using comparative transcriptomic analyses of two highly metastatic (C1 and C6) and two poorly metastatic clonal variants (C4 and C5) isolated from the metastatic OS cell line, KHOS. Using this approach, we determined that the metastatic phenotype correlated with overexpression of thioredoxin reductase 2 (TXNRD2) or vascular endothelial growth factor (VEGF). Validation in patient biopsies confirmed TXNRD2 and VEGF targets were highly expressed in 29-42% of metastatic OS patient biopsies, with no detectable expression in non-malignant bone or samples from OS patients with localised disease. Auranofin (AF) was used to selectively target and inhibit thioredoxin reductase (TrxR). At low doses, AF was able to inhibit TrxR activity without a significant effect on cell viability whereas at higher doses, AF could induce ROS-dependent apoptosis. AF treatment, in vivo, significantly reduced the development of pulmonary metastasis and we provide evidence that this effect may be due to an AF-dependent increase in cellular ROS. Thus, TXNRD2 may represent a novel druggable target that could be deployed to reduce the development of fatal pulmonary metastases in patients with OS.

| S-EPMC4808036 | biostudies-literature

Oncogenic MNK signalling regulates the metastasis suppressor NDRG1.

Project description:The protein N-myc down-regulated gene 1 (NDRG1) represses tumour metastasis. It is phosphorylated at several sites by serum and glucocorticoid-regulated kinase 1 (SGK1). Here we show that NDRG1 is also regulated by the oncogenic MAP kinase-interacting kinase (MNK) pathway, a target for cancer therapy.Inhibiting MNKs increases the expression of NDRG1 protein and mRNA in breast cancer cells. MNK inhibition also decreases the phosphorylation of NDRG1. Phosphorylation of NDRG1 is reduced in cells lacking MNK1, but not MNK2-knockout cells, indicating that NDRG1 phosphorylation is a specific target for MNK1. However, MNK1 cannot directly phosphorylate NDRG1 in vitro, indicating that additional signalling connections are involved. Taken together, our data indicate that MNK signaling regulates NDRG1 at transcriptional and post-translational levels.We show that SGK1 phosphorylates MNK1 at a conserved site, which represses its activity. NDRG1, SGK1 and the MNKs are implicated in cell migration and metastasis. As expected, knocking-down NDRG1 promoted cell migration. However, whereas MNK inhibition impairs these processes irrespective of NDRG1 levels, SGK inhibition only did so in NDRG1-depleted cells. Thus, MNKs and SGK affect migration/invasion through distinct mechanisms.Our data reveal several novel connections between signalling pathways important for tumour biology.

| S-EPMC5542254 | biostudies-literature

Pleiotropic tumor suppressor functions of WWOX antagonize metastasis.

Project description:Tumor progression and metastasis are the major causes of death among cancer associated mortality. Metastatic cells acquire features of migration and invasion and usually undergo epithelia-mesenchymal transition (EMT). Acquirement of these various hallmarks rely on different cellular pathways, including TGF-β and Wnt signaling. Recently, we reported that WW domain-containing oxidoreductase (WWOX) acts as a tumor suppressor and has anti-metastatic activities involving regulation of several key microRNAs (miRNAs) in triple-negative breast cancer (TNBC). Here, we report that WWOX restoration in highly metastatic MDA-MB435S cancer cells alters mRNA expression profiles; further, WWOX interacts with various proteins to exert its tumor suppressor function. Careful alignment and analysis of gene and miRNA expression in these cells revealed profound changes in cellular pathways mediating adhesion, invasion and motility. We further demonstrate that WWOX, through regulation of miR-146a levels, regulates SMAD3, which is a member of the TGF-β signaling pathway. Moreover, proteomic analysis of WWOX partners revealed regulation of the Wnt-signaling activation through physical interaction with Disheveled. Altogether, these findings underscore a significant role for WWOX in antagonizing metastasis, further highlighting its role and therapeutic potential in suppressing tumor progression.

| S-EPMC7162874 | biostudies-literature

Ras Suppressor-1 (RSU1) in Cancer Cell Metastasis: A Tale of a Tumor Suppressor.

Project description:Cancer is a multifactorial disease responsible for millions of deaths worldwide. It has a strong genetic background, as mutations in oncogenes or tumor suppressor genes contribute to the initiation of cancer development. Integrin signaling as well as the signaling pathway of Ras oncogene, have been long implicated both in carcinogenesis and disease progression. Moreover, they have been involved in the promotion of metastasis, which accounts for the majority of cancer-related deaths. Ras Suppressor-1 (RSU1) was identified as a suppressor of Ras-induced transformation and was shown to localize to cell-extracellular matrix adhesions. Recent findings indicate that its expression is elevated in various cancer types, while its role in regulating metastasis-related cellular processes remains largely unknown. Interestingly, there is no in vivo work in the field to date, and thus, all relevant knowledge stems from in vitro studies. In this review, we summarize recent studies using breast, liver and brain cancer cell lines and highlight the role of RSU1 in regulating cancer cell invasion.

| S-EPMC7312364 | 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