Targeting metastasis stem cells through the fatty acid receptor CD36
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE72939 | GEO | 2016/12/16
SECONDARY ACCESSION(S): PRJNA295964
REPOSITORIES: GEO
Similar Datasets
Project description:Metastasis is the leading cause of cancer-related deaths. For most human cancers, the identity of the cells that initiate and promote metastasis is still unknown, hampering our ability to develop therapies to prevent or inhibit the spread of tumour cells to distant sites. Using an orthotopic model of human oral squamous cell carcinoma (OSCC), we have now identified a subpopulation of CD44bright cells within the primary lesion with the highest potential to develop lymph node and lung metastasis. This population is slow-cycling, expresses high levels of the receptor CD36 at the cell membrane and relies on fatty acid metabolism to thrive in lymph nodes and bronchoalveolar environments. Importantly, inhibition of CD36 by either shRNA or neutralizing monoclonal antibodies severely impairs metastatic spread of primary OSCC patient samples and established cell lines. Further underscoring its importance, CD36 overexpression in poorly disseminating tumours confers an aggressive metastatic behaviour. Analyses of public gene expression data indicate that the presence of the signature-defining CD36+ cells also strongly correlates with a poor prognosis in patients with lung SCC, ovarian cancer, bladder cancer, or luminal breast cancer. By identifying metastasis-promoting cells and then targeting them with CD36 inhibition, novel anti-metastatic therapies could be developed for patients with these types of tumours.
2016-12-16 | GSE83276 | GEO
Project description:Metastasis is the leading cause of cancer-related deaths. For most human cancers, the identity of the cells that initiate and promote metastasis is still unknown, hampering our ability to develop therapies to prevent or inhibit the spread of tumour cells to distant sites. Using an orthotopic model of human oral squamous cell carcinoma (OSCC), we have now identified a subpopulation of CD44bright cells within the primary lesion with the highest potential to develop lymph node and lung metastasis. This population is slow-cycling, expresses high levels of the receptor CD36 at the cell membrane and relies on fatty acid metabolism to thrive in lymph nodes and bronchoalveolar environments. Importantly, inhibition of CD36 by either shRNA or neutralizing monoclonal antibodies severely impairs metastatic spread of primary OSCC patient samples and established cell lines. Further underscoring its importance, CD36 overexpression in poorly disseminating tumours confers an aggressive metastatic behaviour. Analyses of public gene expression data indicate that the presence of the signature-defining CD36+ cells also strongly correlates with a poor prognosis in patients with lung SCC, ovarian cancer, bladder cancer, or luminal breast cancer. By identifying metastasis-promoting cells and then targeting them with CD36 inhibition, novel anti-metastatic therapies could be developed for patients with these types of tumours.
2016-12-16 | GSE72938 | GEO
Project description:Metastasis is the leading cause of cancer-related deaths. For most human cancers, the identity of the cells that initiate and promote metastasis is still unknown, hampering our ability to develop therapies to prevent or inhibit the spread of tumour cells to distant sites. Using an orthotopic model of human oral squamous cell carcinoma (OSCC), we have now identified a subpopulation of CD44bright cells within the primary lesion with the highest potential to develop lymph node and lung metastasis. This population is slow-cycling, expresses high levels of the receptor CD36 at the cell membrane and relies on fatty acid metabolism to thrive in lymph nodes and bronchoalveolar environments. Importantly, inhibition of CD36 by either shRNA or neutralizing monoclonal antibodies severely impairs metastatic spread of primary OSCC patient samples and established cell lines. Further underscoring its importance, CD36 overexpression in poorly disseminating tumours confers an aggressive metastatic behavior. Analyses of public gene expression data indicate that the presence of the signature-defining CD36+ cells also strongly correlates with a poor prognosis in patients with lung SCC, ovarian cancer, bladder cancer, or luminal breast cancer. By identifying metastasis-promoting cells and then targeting them with CD36 inhibition, novel anti-metastatic therapies could be developed for patients with these types of tumours.
2016-12-16 | GSE72935 | GEO
Project description:Metastasis is the leading cause of cancer-related deaths. For most human cancers, the identity of the cells that initiate and promote metastasis is still unknown, hampering our ability to develop therapies to prevent or inhibit the spread of tumour cells to distant sites. Using an orthotopic model of human oral squamous cell carcinoma (OSCC), we have now identified a subpopulation of CD44bright cells within the primary lesion with the highest potential to develop lymph node and lung metastasis. This population is slow-cycling, expresses high levels of the receptor CD36 at the cell membrane and relies on fatty acid metabolism to thrive in lymph nodes and bronchoalveolar environments. Importantly, inhibition of CD36 by either shRNA or neutralizing monoclonal antibodies severely impairs metastatic spread of primary OSCC patient samples and established cell lines. Further underscoring its importance, CD36 overexpression in poorly disseminating tumours confers an aggressive metastatic behaviour. Analyses of public gene expression data indicate that the presence of the signature-defining CD36+ cells also strongly correlates with a poor prognosis in patients with lung SCC, ovarian cancer, bladder cancer, or luminal breast cancer. By identifying metastasis-promoting cells and then targeting them with CD36 inhibition, novel anti-metastatic therapies could be developed for patients with these types of tumours.
2016-12-16 | GSE83346 | GEO
Project description:Targeting metastasis stem cells through the fatty acid receptor CD36
| PRJNA295964 | ENA
Project description:Nuclear receptors (NRs) are a superfamily of transcription factors which sense hormonal signals or nutrients to regulate various biological events, including development, reproduction, and metabolism. Here, this study identifies nuclear receptor subfamily 2, group F, member 6 (NR2F6), as an important regulator of hepatic triglyceride (TG) homeostasis and causal factor in the development of non-alcoholic fatty liver disease (NAFLD). Adeno-associated virus (AAV)-mediated overexpression of NR2F6 in the liver promotes TG accumulation in lean mice, while hepatic-specific suppression of NR2F6 improves obesity-associated hepatosteatosis, insulin resistance, and methionine and choline-deficient (MCD) diet-induced non-alcoholic steatohepatitis (NASH). Mechanistically, the fatty acid translocase CD36 is identified as a transcriptional target of NR2F6 to mediate its steatotic role. NR2F6 is able to bind directly onto the CD36 promoter region in hepatocytes and increases the enrichment of nuclear receptor coactivator 1 (SRC-1) and histone acetylation at its promoter. Of pathophysiological significance, NR2F6 is significantly upregulated in the livers of obese mice and NAFLD patients. Moreover, treatment with metformin decreases NR2F6 expression in obese mice, resulting in suppression of CD36 and reduced hepatic TG contents. Therefore, these results provide evidence for an unpredicted role of NR2F6 that contributes to liver steatosis and suggest that NR2F6 antagonists may present a therapeutic strategy for reversing or treating NAFLD/NASH pathogenesis.
| S-EPMC7610302 | biostudies-literature
Project description:Metastasis is the primary cause of death in patients with advanced cancer. Recently, a high-fat diet was shown to specifically promote the metastatic potential of specific cancer cells in a CD36-dependent manner. However, the molecular basis of the fatty acid (FA)-induced upregulation of CD36 has remained unclear. Methods: RT-qPCR, FACS analysis, immunoblotting and immunohistochemistry, as well as retrieving TCGA database, were carried out to quantitate CD36 expression in gastric cancer (GC) tissues and cell lines. Transwell assay and xenografts were used to assess cell metastasis abilities in vitro and in vivo after indicated treatment. Luciferase reporter assay was carried out to evaluate the changes in signaling pathways when O-GlcNAcylation level was increased in GC cells and in vitro O-GlcNAcylation assay was utilized for wild and mutant types of CD36 protein to explore the potential O-GlcNAcylation sites. Results: High CD36 expression is a predictor of poor survival and promotes metastasis of GC cells and the use of neutralizing antibodies to block CD36 inhibits GC metastasis in mice. FA or a HFD promotes the metastatic potential of GC cells by upregulating CD36 via increasing the O-GlcNAcylation level. Increased O-GlcNAcylation levels promote the transcription of CD36 by activating the NF-κB pathway and also increase its FA uptake activity by directly modifying CD36 at S468 and T470. Conclusion: FA-induced hyper-O-GlcNAcylation promotes the transcription and function of CD36 by activating the NF-κB pathway and directly modifying CD36 at S468 and T470, which drives GC metastasis.
| S-EPMC6691574 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-12-31 | GSE216670 | GEO
Project description:Metabolic reprogramming is a new hallmark of cancer but it remains poorly defined in hepatocellular carcinogenesis (HCC). The fatty acid receptor CD36 is associated with both lipid and glucose metabolism in the liver. However, the role of CD36 in metabolic reprogramming in the progression of HCC still remains to be elucidated. In the present study, we found that CD36 is highly expressed in human HCC as compared with non-tumor hepatic tissue. CD36 overexpression promoted the proliferation, migration, invasion, and in vivo tumor growth of HCC cells, whereas silencing CD36 had the opposite effects. By analysis of cell metabolic phenotype, CD36 expression showed a positive association with extracellular acidification rate, a measure of glycolysis, instead of oxygen consumption rate. Further experiments verified that overexpression of CD36 resulted in increased glycolysis flux and lactic acid production. Mechanistically, CD36 induced mTOR-mediated oncogenic glycolysis via activation of Src/PI3K/AKT signaling axis. Pretreatment of HCC cells with PI3K/AKT/mTOR inhibitors largely blocked the tumor-promoting effect of CD36. Our findings suggest that CD36 exerts a stimulatory effect on HCC growth and metastasis, through mediating aerobic glycolysis by the Src/PI3K/AKT/mTOR signaling pathway.
| S-EPMC7997878 | biostudies-literature
Project description:Background & aimsMolecular mechanisms by which hypoxia might contribute to hepatosteatosis, the earliest stage in non-alcoholic fatty liver disease (NAFLD) pathogenesis, remain still to be elucidated. We aimed to assess the impact of hypoxia-inducible factor 2α (HIF2α) on the fatty acid translocase CD36 expression and function in vivo and in vitro.MethodsCD36 expression and intracellular lipid content were determined in hypoxic hepatocytes, and in hypoxic CD36- or HIF2α -silenced human liver cells. Histological analysis, and HIF2α and CD36 expression were evaluated in livers from animals in which von Hippel-Lindau (Vhl) gene is inactivated (Vhlf/f -deficient mice), or both Vhl and Hif2a are simultaneously inactivated (Vhlf/f Hif2α/f -deficient mice), and from 33 biopsy-proven NAFLD patients and 18 subjects with histologically normal liver.ResultsIn hypoxic hepatocytes, CD36 expression and intracellular lipid content were augmented. Noteworthy, CD36 knockdown significantly reduced lipid accumulation, and HIF2A gene silencing markedly reverted both hypoxia-induced events in hypoxic liver cells. Moreover livers from Vhlf/f -deficient mice showed histologic characteristics of non-alcoholic steatohepatitis (NASH) and increased CD36 mRNA and protein amounts, whereas both significantly decreased and NASH features markedly ameliorated in Vhlf/f Hif2αf/f -deficient mice. In addition, both HIF2α and CD36 were significantly overexpressed within the liver of NAFLD patients and, interestingly, a significant positive correlation between hepatic transcript levels of CD36 and erythropoietin (EPO), a HIF2α -dependent gene target, was observed in NAFLD patients.ConclusionsThis study provides evidence that HIF2α drives lipid accumulation in human hepatocytes by upregulating CD36 expression and function, and could contribute to hepatosteatosis setup.
| S-EPMC7539965 | biostudies-literature