A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor

The intracellular signaling events causing tumor cells to become metastatic are not well understood. N-cadherin and FGF-2 synergistically increase migration, invasion, and secretion of extracellular proteases in breast tumor cells. Here, we define a metastatic signaling cascade activated by N-cadherin and FGF-2. In the presence of N-cadherin, FGF-2 caused sustained activation of the MAPK-ERK pathway, leading to MMP-9 gene transcription and cellular invasion. N-cadherin prevented the FGF receptor (FGFR) from undergoing ligand-induced internalization, resulting in increased FGFR-1 stability. Association of FGFR-1 with N-cadherin was mediated by the first two Ig-like domains of FGFR-1. These results suggest that protection of the FGFR-1 from ligand-induced downregulation by N-cadherin enhances receptor signaling and provides a mechanism by which tumor cells can acquire metastatic properties

A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor

The intracellular signaling events causing tumor cells to become metastatic are not well understood. N-cadherin and FGF-2 synergistically increase migration, invasion, and secretion of extracellular proteases in breast tumor cells. Here, we define a metastatic signaling cascade activated by N-cadherin and FGF-2. In the presence of N-cadherin, FGF-2 caused sustained activation of the MAPK-ERK pathway, leading to MMP-9 gene transcription and cellular invasion. N-cadherin prevented the FGF receptor (FGFR) from undergoing ligand-induced internalization, resulting in increased FGFR-1 stability. Association of FGFR-1 with N-cadherin was mediated by the first two Ig-like domains of FGFR-1. These results suggest that protection of the FGFR-1 from ligand-induced downregulation by N-cadherin enhances receptor signaling and provides a mechanism by which tumor cells can acquire metastatic properties

Developmental and gender-related trends of intra-talker variability in consonant production

This study investigates the effect of age and gender on the internal structure, cross-category distance, and discriminability of phonemic categories for two contrasts varying in fricative place of articulation (/s/-/ʃ/) and stop voicing (/b/-/p/) in word-initial tokensspoken by adults and normally-developing children aged 9 to 14 years. Vast between- and within-talker variability was observed, with 16% of speakers of all ages exhibiting some degree of overlap between phonemic categories—a possible contribution to the range of talker intelligibility found in the literature. Females of all ages produced farther and thus more discriminable categories than males, though gender-marking for fricative between-category distance did not emerge until approximately 11 years of age. Children produced farther yet also much more dispersed categories than adults, with increasing discriminability with age, such that by age 13, children’s categories were no less discriminable than those of adults. However, children’s ages did not predict category distance or dispersion, indicating that convergence on adult-like category structure must occur later in adolescence

DiapixUK: task materials for the elicitation of multiple spontaneous speech dialogs

The renewed focus of attention on investigating spontaneous speech samples in speech and language research has increased the need for recordings of speech in interactive settings. The DiapixUK task is a new and extended set of picture materials based on the Diapix task by Van Engen et al. (2010) where two people are recorded while conversing to solve a ‘spot the difference’ task. The new task materials allow for multiple recordings of the same speaker pairs due to a larger set of picture pairs which have a number of tested features: equal difficulty across all twelve picture pairs, no learning effect of completing more than one picture task and balanced contributions from both speakers. The new materials also provide extra flexibility making them useful in a wide range of research projects; they are multi-layered electronic images that can be adapted to suit different research needs. This paper presents details of the development of the DiapixUK materials along with data taken from a large corpus of spontaneous speech which demonstrate its new features. Current and potential applications of the task are also discussed

Effective DNA/RNA Co-Extraction for Analysis of MicroRNAs, mRNAs, and Genomic DNA from Formalin-Fixed Paraffin-Embedded Specimens

Background: Retrospective studies of archived human specimens, with known clinical follow-up, are used to identify predictive and prognostic molecular markers of disease. Due to biochemical differences, however, formalin-fixed paraffinembedded (FFPE) DNA and RNA have generally been extracted separately from either different tissue sections or from the same section by dividing the digested tissue. The former limits accurate correlation whilst the latter is impractical when utilizing rare or limited archived specimens. Principal Findings: For effective recovery of genomic DNA and total RNA from a single FFPE specimen, without splitting the proteinase-K digested tissue solution, we optimized a co-extraction method by using TRIzol and purifying DNA from the lower aqueous and RNA from the upper organic phases. Using a series of seven different archived specimens, we evaluated the total amounts of genomic DNA and total RNA recovered by our TRIzol-based co-extraction method and compared our results with those from two commercial kits, the Qiagen AllPrep DNA/RNA FFPE kit, for co-extraction, and the Ambion RecoverAll TM Total Nucleic Acid Isolation kit, for separate extraction of FFPE-DNA and-RNA. Then, to accurately assess the quality of DNA and RNA co-extracted from a single FFPE specimen, we used qRT-PCR, gene expression profiling and methylation assays to analyze microRNAs, mRNAs, and genomic DNA recovered from matched fresh and FFPE MCF10A cells. These experiments show that the TRIzol-based co-extraction method provides larger amounts of FFPE-DNA and –RNA tha

Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer

In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression