Interactions between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment significantly influence cancer growth and metastasis. Transforming growth factor-β (TGF-β) is ...known to be a critical mediator of the CAF phenotype, and osteopontin (OPN) expression in tumors is associated with more aggressive phenotypes and poor patient outcomes. The potential link between these two pathways has not been previously addressed. Utilizing in vitro studies using human mesenchymal stem cells (MSCs) and MDA-MB231 (OPN+) and MCF7 (OPN-) human breast cancer cell lines, we demonstrate that OPN induces integrin-dependent MSC expression of TGF-β1 to mediate adoption of the CAF phenotype. This OPN-TGF-β1 pathway requires the transcription factor, myeloid zinc finger 1 (MZF1). In vivo studies with xenotransplant models in NOD-scid mice showed that OPN expression increases cancer growth and metastasis by mediating MSC-to-CAF transformation in a process that is MZF1 and TGF-β1 dependent. We conclude that tumor-derived OPN engenders MSC-to-CAF transformation in the microenvironment to promote tumor growth and metastasis via the OPN-MZF1-TGF-β1 pathway.
Summary
This paper presents an algorithm and a fully coupled hydromechanical‐fracture formulation for the simulation of three‐dimensional nonplanar hydraulic fracture propagation. The propagation ...algorithm automatically estimates the magnitude of time steps such that a regularized form of Irwin's criterion is satisfied along the predicted 3‐D fracture front at every fracture propagation step.
A generalized finite element method is used for the discretization of elasticity equations governing the deformation of the rock, and a finite element method is adopted for the solution of the fluid flow equation on the basis of Poiseuille's cubic law. Adaptive mesh refinement is used for discretization error control, leading to significantly fewer degrees of freedom than available nonadaptive methods. An efficient computational scheme to handle nonlinear time‐dependent problems with adaptive mesh refinement is presented. Explicit fracture surface representations are used to avoid mapping of 3‐D solutions between generalized finite element method meshes. Examples demonstrating the accuracy, robustness, and computational efficiency of the proposed formulation, regularized Irwin's criterion, and propagation algorithm are presented.
Interactions between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment significantly influence cancer growth and metastasis. Transforming growth factor- beta (TGF- ...beta ) is known to be a critical mediator of the CAF phenotype, and osteopontin (OPN) expression in tumors is associated with more aggressive phenotypes and poor patient outcomes. The potential link between these two pathways has not been previously addressed. Utilizing in vitro studies using human mesenchymal stem cells (MSCs) and MDA-MB231 (OPN+) and MCF7 (OPN-) human breast cancer cell lines, we demonstrate that OPN induces integrin-dependent MSC expression of TGF- beta 1 to mediate adoption of the CAF phenotype. This OPN-TGF- beta 1 pathway requires the transcription factor, myeloid zinc finger 1 (MZF1). In vivo studies with xenotransplant models in NOD-scid mice showed that OPN expression increases cancer growth and metastasis by mediating MSC-to-CAF transformation in a process that is MZF1 and TGF- beta 1 dependent. We conclude that tumor-derived OPN engenders MSC-to-CAF transformation in the microenvironment to promote tumor growth and metastasis via the OPN-MZF1-TGF- beta 1 pathway.
Oligomerization of membrane proteins in response to lipid binding has a critical role in many cell-signalling pathways but is often difficult to define or predict. Here we report the development of a ...mass spectrometry platform to determine simultaneously the presence of interfacial lipids and oligomeric stability and to uncover how lipids act as key regulators of membrane-protein association. Evaluation of oligomeric strength for a dataset of 125 α-helical oligomeric membrane proteins reveals an absence of interfacial lipids in the mass spectra of 12 membrane proteins with high oligomeric stability. For the bacterial homologue of the eukaryotic biogenic transporters (LeuT, one of the proteins with the lowest oligomeric stability), we found a precise cohort of lipids within the dimer interface. Delipidation, mutation of lipid-binding sites or expression in cardiolipin-deficient Escherichia coli abrogated dimer formation. Molecular dynamics simulation revealed that cardiolipin acts as a bidentate ligand, bridging across subunits. Subsequently, we show that for the Vibrio splendidus sugar transporter SemiSWEET, another protein with low oligomeric stability, cardiolipin shifts the equilibrium from monomer to functional dimer. We hypothesized that lipids are essential for dimerization of the Na
/H
antiporter NhaA from E. coli, which has the lowest oligomeric strength, but not for the substantially more stable homologous Thermus thermophilus protein NapA. We found that lipid binding is obligatory for dimerization of NhaA, whereas NapA has adapted to form an interface that is stable without lipids. Overall, by correlating interfacial strength with the presence of interfacial lipids, we provide a rationale for understanding the role of lipids in both transient and stable interactions within a range of α-helical membrane proteins, including G-protein-coupled receptors.
We provide a post-mission assessment of the science and data from the Electric and Magnetic Field Instrument Suite and Integrated Science (EMFISIS) investigation on the NASA Van Allen Probes mission. ...An overview of important scientific results is presented, covering all of the key wave modes and DC magnetic fields measured by EMFISIS. Discussion of the data products, which are publicly available, follows to provide users with guidance on characteristics and known issues of the measurements. We present guidance on the correct use of derived products, in particular, the wave-normal analysis (WNA) which yields fundamental wave properties such as polarization, ellipticity, and Poynting flux. We also give information about the plasma density derived from measuring the upper hybrid line in the inner magnetosphere.
Recurrent mutations in core splicing factors have been reported in several clonal disorders, including cancers. Mutations in SF3B1, a component of the U2 splicing complex, are the most common. SF3B1 ...mutations are associated with aberrant pre-mRNA splicing using cryptic 3' splice sites (3'SSs), but the mechanism of their selection is not clear. To understand how cryptic 3'SSs are selected, we performed comprehensive analysis of transcriptome-wide changes to splicing and gene expression associated with SF3B1 mutations in patient samples as well as an experimental model of inducible expression. Hundreds of cryptic 3'SS were detectable across the genome in cells expressing mutant SF3B1. These 3'SS are typically sequestered within RNA secondary structures and poorly accessible compared with their corresponding canonical 3'SS. We hypothesized that these cryptic 3'SS are inaccessible during normal splicing catalysis and that this constraint is overcome in spliceosomes containing mutant SF3B1. This model of secondary structure-dependent selection of cryptic 3'SS was found across multiple clonal processes associated with SF3B1 mutations (myelodysplastic syndrome and chronic lymphocytic leukemia). We validated our model predictions in mini-gene splicing assays. Additionally, we found deregulated expression of proteins with relevant functions in splicing factor-related diseases both in association with aberrant splicing and without corresponding splicing changes. Our results show that SF3B1 mutations are associated with a distinct splicing program shared across multiple clonal processes and define a biochemical mechanism for altered 3'SS choice.
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