High levels of NF-YAl drives EMT in Claudinlow tumors
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ABSTRACT:
PROVIDER: PRJNA858254 | ENA |
REPOSITORIES: ENA
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Project description:NF-Y is a trimeric transcription factor whose binding site -the CCAAT box- is enriched in cancer-promoting genes. The regulatory subunit, the sequence-specificity conferring NF-YA, comes in two major isoforms, NF-YA long (NF-YAl) and short (NF-YAs). Extensive expression analysis in epithelial cancers determined two features: widespread overexpression and changes in NF-YAl/NF-Ys ratios (NF-YAr) in tumors with EMT features. We performed wet and in silico experiments to explore the role of the NF-YA isoforms in breast -BRCA- and gastric -STAD- cancers. We generated clones of two Claudinlow BRCA lines BT549 and SUM159PT ablated of exon-3, thus shifting expression from NF-YAl to NF-YAs. Edited clones show normal growth, but reduced migratory capacities in vitro, and ability to metastatize in vivo. Using TCGA, including upon deconvolution of scRNA-seq data, we formalize the clinical importance of high NF-YAr, associated to EMT genes and cell populations. We derive a novel, 158 genes signature common to BRCA and STAD Claudinlow tumors. Finally, we identify splicing factors associated to high NF-YAr, further validating RBFOX2 as promoting expression of NF-YAl with wet experiments. In conclusion, these data bring three relevant results: (i) concerning Claudinlow tumors, the definition and clinical implications of NF-YAr and the 158 genes signature; (ii) genetic evidence of a role of exon-3 28 aminoacids, empowering NF-YAl with EMT-driving features in BRCA. (iii) The definition of a set of splicing factors fine-tuning the levels of NF-YA isoforms.
2023-01-28 | GSE208088 | GEO
Project description:The present study is aimed at detecting and measuring mRNA levels of genes involved in epithelial to mesenchymal transition (EMT) in biological samples, i.e. in peripheral blood samples of colorectal cancer (CRC) patients and healthy controls, to determine the presence of disease, its progression and risk of recurrence.
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Project description:Aberrant NF-kB signaling fuels tumor growth in multiple human cancer types including both hematologic and solid malignancies. Chronic elevated alternative NF-kB signaling can be modeled in transgenic mice upon activation of a conditional NF-kB-inducing kinase (NIK) allele lacking the regulatory TRAF3 binding domain (NT3). Here, we report that expression of NT3 in the mesenchymal lineage with Osterix (Osx/Sp7)-Cre or Fibroblast Specific Protein (Fsp1)-Cre caused subcutaneous, soft tissue tumors. These tumors displayed significantly shorter latency and a greater multiple incidence rate in Fsp1-Cre;NT3 compared to Osx-Cre;NT3 mice, regardless of sex. Histological assessment revealed poorly differentiated solid tumors with some spindled patterns, as well as robust RelB (Relb) immunostaining, confirming activation of alternative NF-kB. Even though NT3 expression also occurs in the osteolineage in Osx-Cre;NT3 mice, we observed no bony lesions. The staining profiles and pattern of Cre expression in the two lines pointed to a mesenchymal tumor origin. Immunohistochemistry revealed that these tumors stain strongly for SMA (Acta2), although vimentin (Vim) staining was uniform only in Osx-Cre;NT3 tumors. Negative CD45 (Ptprc) and S100 immunostains precluded hematopoietic and melanocytic origins, respectively, while positive staining for CK19 (Krt19), typically associated with epithelia, was found in subpopulations of both tumors. Principal component, differential expression, and gene ontology analyses revealed that NT3 tumors are distinct from normal mesenchymal tissues and are enriched for NF-kB related biological processes. We conclude that constitutive activation of the alternative NF-kB pathway in the mesenchymal linage drives spontaneous sarcoma and provides a novel mouse model for NF-kB related sarcomas.
2020-09-25 | GSE158479 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE32727: EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors [human] GSE32904: EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors [mouse] Refer to individual Series
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Project description:NF-Y is a trimeric transcription factor whose binding site -the CCAAT box- is enriched in cancer-promoting genes. The regulatory subunit, the sequence-specificity conferring NF-YA, comes in two major isoforms, NF-YA long (NF-YAl) and short (NF-YAs). Extensive expression analysis in epithelial cancers determined two features: widespread overexpression and changes in NF-YAl/NF-YAs ratios (NF-YAr) in tumours with EMT features. We performed wet and in silico experiments to explore the role of the isoforms in breast -BRCA- and gastric -STAD- cancers. We generated clones of two Claudinlow BRCA lines SUM159PT and BT549 ablated of exon-3, thus shifting expression from NF-YAl to NF-YAs. Edited clones show normal growth but reduced migratory capacities in vitro and ability to metastatize in vivo. Using TCGA, including upon deconvolution of scRNA-seq data, we formalize the clinical importance of high NF-YAr, associated to EMT genes and cell populations. We derive a novel, prognostic 158 genes signature common to BRCA and STAD Claudinlow tumours. Finally, we identify splicing factors associated to high NF-YAr, validating RBFOX2 as promoting expression of NF-YAl. These data bring three relevant results: (i) the definition and clinical implications of NF-YAr and the 158 genes signature in Claudinlow tumours; (ii) genetic evidence of 28 amino acids in NF-YAl with EMT-promoting capacity; (iii) the definition of selected splicing factors associated to NF-YA isoforms.
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Project description:Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-B activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Remarkably, inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-B inactivation and further transformed by constitutive NF-B activation. Our study establishes a central role for microglial NF-B signaling in mediating tau spreading and toxicity in tauopathy.
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