Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA162691 | ENA |
REPOSITORIES: ENA
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Project description:While growth factor-independent signaling and proliferation are well-established hallmarks of cancer, little is known regarding growth factor-independent changes in gene expression which occur downstream from oncogenes. The PI3K pathway is one of the most commonly misregulated signaling pathways in human cancers. Here, MCF10A cells expressing the two most common PI3K mutations, PIK3CA E545K and H1047R, were used to identify the repertoire of genes altered by oncogenic PI3K mutations following growth factor deprivation. This gene set most closely correlated with gene signatures from claudin-low and basal-like breast tumors, and categorical enrichment analyses suggested that NF-kB target genes were dramatically upregulated by these mutations. An IKKb inhibitor was used to identify the subset of PI3K-driven genes that is NF-kB dependent. Interestingly, virtually all of these NF-kB dependent genes were secreted proteins, suggesting a paracrine role for this gene set. Among these genes was IL-6, a cytokine frequently expressed in tumors which plays a critical role in generating a tumor-promoting microenvironment. Consistent with this, conditioned media from cells expressing the E545K or H1047R mutations led to increased STAT3 activation in recipient THP-1 monocytes or normal epithelial cells in a NF-kB and IL-6-dependent manner. Together, these data describe a PI3K-driven, NF-kB-dependent gene expression profile which may play a critical role in promoting a microenvironment amenable to tumor progression. 39 normal cell lines vs treated cell lines for micorarray analysis
2012-04-30 | E-GEOD-33403 | biostudies-arrayexpress
Project description:While growth factor-independent signaling and proliferation are well-established hallmarks of cancer, little is known regarding growth factor-independent changes in gene expression which occur downstream from oncogenes. The PI3K pathway is one of the most commonly misregulated signaling pathways in human cancers. Here, MCF10A cells expressing the two most common PI3K mutations, PIK3CA E545K and H1047R, were used to identify the repertoire of genes altered by oncogenic PI3K mutations following growth factor deprivation. This gene set most closely correlated with gene signatures from claudin-low and basal-like breast tumors, and categorical enrichment analyses suggested that NF-kB target genes were dramatically upregulated by these mutations. An IKKb inhibitor was used to identify the subset of PI3K-driven genes that is NF-kB dependent. Interestingly, virtually all of these NF-kB dependent genes were secreted proteins, suggesting a paracrine role for this gene set. Among these genes was IL-6, a cytokine frequently expressed in tumors which plays a critical role in generating a tumor-promoting microenvironment. Consistent with this, conditioned media from cells expressing the E545K or H1047R mutations led to increased STAT3 activation in recipient THP-1 monocytes or normal epithelial cells in a NF-kB and IL-6-dependent manner. Together, these data describe a PI3K-driven, NF-kB-dependent gene expression profile which may play a critical role in promoting a microenvironment amenable to tumor progression.
2012-05-01 | GSE33403 | GEO
Project description:Mutations in KRAS occur in a variety of tumors of epithelial origin, driving the oncogenic phenotype.The NF-kB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently TAK1, an upstream regulator of IKK which controls canonical NF-kB, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS+ colorectal cancer cell growth and survival. Here we show that GSK-3alpha is upregulated by KRAS leading to interaction with TAK1 to stabilize the TAK1/TAB complex to promote IKK activity. Additionally, GSK-3alpha is required for promoting critical non-canonical NF-kB signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with loss of expression of genes such as c-myc and TERT. These data identify GSK-3alpha as a key downstream effector of oncogenic RAS via its ability to coordinately regulate distinct NF-kB signaling pathways GSK-3 inhibition at 2 and 8 hours
2013-05-31 | E-GEOD-42559 | biostudies-arrayexpress
Project description:Mutations in KRAS occur in a variety of tumors of epithelial origin, driving the oncogenic phenotype.The NF-kB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently TAK1, an upstream regulator of IKK which controls canonical NF-kB, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS+ colorectal cancer cell growth and survival. Here we show that GSK-3alpha is upregulated by KRAS leading to interaction with TAK1 to stabilize the TAK1/TAB complex to promote IKK activity. Additionally, GSK-3alpha is required for promoting critical non-canonical NF-kB signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with loss of expression of genes such as c-myc and TERT. These data identify GSK-3alpha as a key downstream effector of oncogenic RAS via its ability to coordinately regulate distinct NF-kB signaling pathways
2013-05-31 | GSE42559 | GEO
Project description:EZH2 has been studied most extensively in the context of PRC2-dependent gene repression. Paradoxically, accumulating evidence indicates non-canonical functions for EZH2 in cancer contexts including promoting gene expression in triple negative breast cancer (TNBC) cells through interactions with the transcription factor NF-kB. We define a genomic profile of EZH2 and NF-kB factor RelA, RelB, and NFKB2/p52 co-localization and positive regulation of a subset of NF-kB targets and genes associated with oncogenic functions in TNBC, which is enriched in patient datasets. We demonstrate interaction between EZH2 and RelA requiring the recently identified EZH2 transactivation domain (TAD), which mediates EZH2 recruitment to and activation of certain NF-kB-dependent genes, and supports downstream stemness phenotypes in TNBC cells. Interestingly, EZH2-NF-kB positive regulation of genes and stemness does not require PRC2. This study provides new insight into pro-oncogenic regulatory functions for EZH2 in breast cancer through PRC2-independent, and NF-kB-dependent regulatory mechanisms.
2023-07-10 | GSE223959 | GEO
Project description:In an effort to identify genes whose expression is regulated by activated PI3K signaling, we performed microarray analysis and subsequent qRT-PCR on an isogenic set of PTEN gene-targeted human cancer cells. Numerous p53 effectors were upregulated following PTEN deletion, including p21, GDF15, PIG3, NOXA, and PLK2. Stable depletion of p53 led to reversion of the gene expression program. Western blots revealed that p53 was stabilized in HCT116 PTEN-/- cells via an Akt1-dependent and p14ARF-independent mechanism. Stable depletion of PTEN in untransformed human fibroblasts and epithelial cells also led to upregulation of p53 and senescent-like growth arrest. Simultaneous depletion of p53 rescued this phenotype, enabling PTEN-depleted cells to continue proliferating. Next, we tested whether oncogenic PIK3CA, like inactivated PTEN, could activate p53. Retroviral expression of oncogenic human PIK3CA in MCF10A cells led to activation of p53 and upregulation of p53-regulated genes. Stable depletion of p53 reversed these PIK3CA-induced expression changes and synergized with oncogenic PIK3CA in inducing anchorage-independent growth. Finally, targeted deletion of an endogenous allele of oncogenic but not wild-type PIK3CA in a human cancer cell line led to a reduction in p53 levels and a decrease in the expression of p53-regulated genes. These studies demonstrate that activation of PI3K signaling by mutations in PTEN or PIK3CA can lead to activation of p53-mediated growth suppression in human cells, indicating that p53 can function as a brake on PIP3-induced mitogenesis during human cancer pathogenesis. Experiment Overall Design: Two HCT116 PTEN+/+ cell lines (parental cells and a clone with random integration of the targeting vector) and three independently-derived HCT116 PTEN-/- cell lines were studied
2008-06-14 | E-GEOD-6263 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It is characterized by activating KRAS mutations and p53 alterations. However, how these mutations alter cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood. Here, we demonstrate that p53R172H enhances tumor growth, establishes a suppressive TME by inducing immune evasion, and blunts the effectiveness of immune checkpoint inhibitors (ICIs). We discovered that the oncogenic function of p53R172H is mediated by upregulation of the immunosuppressive chemokine Cxcl1. Mechanistically, we show that p53R172H binds to the distal enhancers of the Cxcl1 gene and increases enhancer activity and Cxcl1 expression. NF-kB also occupies Cxcl1 enhancers, and p53R172H binds these enhancers in an NF-kB-dependent manner, suggesting a role of NF-kB in commuting p53R172H to the Cxcl1 enhancers. Our findings elucidate how a common mutation in a critical tumor-suppressor gene exploits enhancers to modulate chemokine gene expression and foster an immunosuppressive TME in PDAC that undermines the efficacy of ICI.
2024-10-09 | GSE275105 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It is characterized by activating KRAS mutations and p53 alterations. However, how these mutations alter cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood. Here, we demonstrate that p53R172H enhances tumor growth, establishes a suppressive TME by inducing immune evasion, and blunts the effectiveness of immune checkpoint inhibitors (ICIs). We discovered that the oncogenic function of p53R172H is mediated by upregulation of the immunosuppressive chemokine Cxcl1. Mechanistically, we show that p53R172H binds to the distal enhancers of the Cxcl1 gene and increases enhancer activity and Cxcl1 expression. NF-kB also occupies Cxcl1 enhancers, and p53R172H binds these enhancers in an NF-kB-dependent manner, suggesting a role of NF-kB in commuting p53R172H to the Cxcl1 enhancers. Our findings elucidate how a common mutation in a critical tumor-suppressor gene exploits enhancers to modulate chemokine gene expression and foster an immunosuppressive TME in PDAC that undermines the efficacy of ICI.
2024-10-09 | GSE275108 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It is characterized by activating KRAS mutations and p53 alterations. However, how these mutations alter cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood. Here, we demonstrate that p53R172H enhances tumor growth, establishes a suppressive TME by inducing immune evasion, and blunts the effectiveness of immune checkpoint inhibitors (ICIs). We discovered that the oncogenic function of p53R172H is mediated by upregulation of the immunosuppressive chemokine Cxcl1. Mechanistically, we show that p53R172H binds to the distal enhancers of the Cxcl1 gene and increases enhancer activity and Cxcl1 expression. NF-kB also occupies Cxcl1 enhancers, and p53R172H binds these enhancers in an NF-kB-dependent manner, suggesting a role of NF-kB in commuting p53R172H to the Cxcl1 enhancers. Our findings elucidate how a common mutation in a critical tumor-suppressor gene exploits enhancers to modulate chemokine gene expression and foster an immunosuppressive TME in PDAC that undermines the efficacy of ICI.
2024-10-09 | GSE275107 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It is characterized by activating KRAS mutations and p53 alterations. However, how these mutations alter cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood. Here, we demonstrate that p53R172H enhances tumor growth, establishes a suppressive TME by inducing immune evasion, and blunts the effectiveness of immune checkpoint inhibitors (ICIs). We discovered that the oncogenic function of p53R172H is mediated by upregulation of the immunosuppressive chemokine Cxcl1. Mechanistically, we show that p53R172H binds to the distal enhancers of the Cxcl1 gene and increases enhancer activity and Cxcl1 expression. NF-kB also occupies Cxcl1 enhancers, and p53R172H binds these enhancers in an NF-kB-dependent manner, suggesting a role of NF-kB in commuting p53R172H to the Cxcl1 enhancers. Our findings elucidate how a common mutation in a critical tumor-suppressor gene exploits enhancers to modulate chemokine gene expression and foster an immunosuppressive TME in PDAC that undermines the efficacy of ICI.
2024-10-09 | GSE275106 | GEO