Comprehensive characterization of 536 patient-derived xenograft models prioritizes candidatesfor targeted treatment

Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs. Here, we report on dynamic genomic landscapes and pharmacogenomic associations, including associations between activating oncogenic events and drugs, correlations between whole-genome duplications and subclone events, and the potential PDX models for NCI-MATCH trials. Lastly, we provide a web portal having comprehensive pan-cancer PDX genomic profiles and source code to facilitate identification of more druggable events and further insights into PDXs' recapitulation of human tumors

Bone Marrow Stromal Cells Modulate Mouse ENT1 Activity and Protect Leukemia Cells from Cytarabine Induced Apoptosis

BACKGROUND: Despite a high response rate to chemotherapy, the majority of patients with acute myeloid leukemia (AML) are destined to relapse due to residual disease in the bone marrow (BM). The tumor microenvironment is increasingly being recognized as a critical factor in mediating cancer cell survival and drug resistance. In this study, we propose to identify mechanisms involved in the chemoprotection conferred by the BM stroma to leukemia cells. METHODS: Using a leukemia mouse model and a human leukemia cell line, we studied the interaction of leukemia cells with the BM microenvironment. We evaluated in vivo and in vitro leukemia cell chemoprotection to different cytotoxic agents mediated by the BM stroma. Leukemia cell apoptosis was assessed by flow cytometry and western blotting. The activity of the equilibrative nucleoside transporter 1 (ENT1), responsible for cytarabine cell incorporation, was investigated by measuring transport and intracellular accumulation of (3)H-adenosine. RESULTS: Leukemia cell mobilization from the bone marrow into peripheral blood in vivo using a CXCR4 inhibitor induced chemo-sensitization of leukemia cells to cytarabine, which translated into a prolonged survival advantage in our mouse leukemia model. In vitro, the BM stromal cells secreted a soluble factor that mediated significant chemoprotection to leukemia cells from cytarabine induced apoptosis. Furthermore, the BM stromal cell supernatant induced a 50% reduction of the ENT1 activity in leukemia cells, reducing the incorporation of cytarabine. No protection was observed when radiation or other cytotoxic agents such as etoposide, cisplatin and 5-fluorouracil were used. CONCLUSION: The BM stroma secretes a soluble factor that significantly protects leukemia cells from cytarabine-induced apoptosis and blocks ENT1 activity. Strategies that modify the chemo-protective effects mediated by the BM microenvironment may enhance the benefit of conventional chemotherapy for patients with AML

Quality of carrots as affected by pre- and postharvest factors and processing

The aim of this review is to provide an update on factors contributing to quality of carrots, with special focus on the role of pre- and postharvest factors and processing. The genetic factor shows the highest impact on quality variables in carrots, causing a 7–11-fold difference between varieties in content of terpenes, β-carotene, magnesium, iron and phenolics as well as a 1–4-fold difference in falcarindiol, bitter taste and sweet taste. Climate-related factors may cause a difference of up to 20-fold for terpenes, 82% for total sugars and 30–40% for β-carotene, sweet taste and bitter taste. Organic farming in comparison with conventional farming has shown 70% higher levels for magnesium and 10% for iron. Low nitrogen fertilisation level may cause up to 100% increase in terpene content, minor increase in dry matter (+4 to +6%) and magnesium (+8%) and reduction in β-carotene content (−8 to −11%). Retail storage at room temperature causes the highest reduction in β-carotene (−70%) and ascorbic acid (−70%). Heat processing by boiling reduces shear force (−300 to −1000%) and crispiness (−67%) as well as content of phenolics (−150%), terpenes (−85%) and total carotenes (−20%) and increases the risk of furan accumulation. Sensory and chemical quality parameters of carrots are determined mainly by genetic and climate-related factors and to a minor extent by cultivation method. Retail temperature and storage atmosphere as well as heating procedure in processing have the highest impact in quality reduction. © 2013 Society of Chemical Industr

Comprehensive molecular characterization of the hippo signaling pathway in cancer

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era

The role of plerixafor in optimizing peripheral blood stem cell mobilization for autologous stem cell transplantation.

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Endothelial α3β1-Integrin Represses Pathological Angiogenesis and Sustains Endothelial-VEGF

Integrin a3ß1 is a major receptor for laminin. The expression levels of laminins-8 and -10 in the basement membrane surrounding blood vessels are known to change during tumor angiogenesis. Although some studies have suggested that certain ligands of a3ß1 can affect angiogenesis either positively or negatively, either a direct in vivo role for a3ß1 in this process or its mechanism of action in endothelial cells during angiogenesis is still unknown. Because the global genetic ablation of a3-integrin results in an early lethal phenotype, we have generated conditional-knockout mice where a3 is deleted specifically in endothelial cells (ec-a3-/-). Here we show that ec-a3-/- mice are viable, fertile, and display enhanced tumor growth, elevated tumor angiogenesis, augmented hypoxia-induced retinal angiogenesis, and increased vascular endothelial growth factor (VEGF)-mediated neovascularization ex vivo and in vivo. Furthermore, our data provide a novel method by which an integrin may regulate angiogenesis. We show that a3ß1 is a positive regulator of endothelial-VEGF and that, surprisingly, the VEGF produced by endothelial cells can actually repress VEGF-receptor 2 (Flk-1) expression. These data, therefore, identify directly that endothelial a3ß1 negatively regulates pathological angiogenesis and implicate an unexpected role for low levels of endothelial-VEGF as an activator of neovascularization

Dual role of pericyte alpha 6 beta 1-integrin in tumour blood vessels

The alpha6beta1-integrin is a major laminin receptor, and formation of a laminin-rich basement membrane is a key feature in tumour blood vessel stabilisation and pericyte recruitment, processes that are important in the growth and maturation of tumour blood vessels. However, the role of pericyte alpha6beta1-integrin in angiogenesis is largely unknown. We developed mice where the alpha6-integrin subunit is deleted in pericytes and examined tumour angiogenesis and growth. These mice had: (1) reduced pericyte coverage of tumour blood vessels; (2) reduced tumour blood vessel stability; (3) increased blood vessel diameter; (4) enhanced blood vessel leakiness, and (5) abnormal blood vessel basement membrane architecture. Surprisingly, tumour growth, blood vessel density and metastasis were not altered. Analysis of retinas revealed that deletion of pericyte alpha6-integrin did not affect physiological angiogenesis. At the molecular level, we provide evidence that pericyte alpha6-integrin controls PDGFRbeta expression and AKT-mTOR signalling. Taken together, we show that pericyte alpha6beta1-integrin regulates tumour blood vessels by both controlling PDGFRbeta and basement membrane architecture. These data establish a novel dual role for pericyte alpha6-integrin as modulating the blood vessel phenotype during pathological angiogenesis