Deciphering the splicing code

Artículo

International network of cancer genome projects

Nature 464, 993-998 (15 April 2010) doi:10.1038/nature08987

International Cancer Genome Consortium
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The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

Cancer remodeling in a basal-like breast cancer metastasis and xenograft.

Nature. April 15, 2010.

Genome remodelling in a basal-like breast cancer metastasis and xenograft

Massively parallel DNA sequencing allows entire genomes to be screened for genetic changes associated with tumour progression. Here, the genomes of four DNA samples from a 44-year-old African-American patient with basal-like breast cancer were analysed. The samples came from peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The findings indicate that cells with a distinct subset of the primary tumour mutation might be selected during metastasis and xenografting.

http://www.nature.com/nature/journal/v464/n7291/abs/nature08987.html

doi:10.1038/nature08989

Transcriptome analyses of mouse and human mammary cell subpopulations reveals multiple conserved genes and pathways

Breast Cancer Research 2010, 12:R21doi:10.1186/bcr2560

Published:	26 March 2010

Introduction

Molecular characterization of the normal epithelial cell types that reside in the mammary gland is an important step towards understanding pathways that regulate self-renewal, lineage commitment and differentiation along the hierarchy. Here we determined the gene expression signatures of four distinct subpopulations isolated from the mouse mammary gland. The epithelial cell signatures were used to interrogate mouse models of mammary tumorigenesis, and compared with their normal human counterpart subsets in order to identify conserved genes and networks.

Methods

RNA was prepared from freshly sorted mouse mammary cell subpopulations (mammary stem cell (MaSC)-enriched, committed luminal progenitor, mature luminal and stromal cell) and used for gene expression profiling analysis on the Illumina platform. Gene signatures were derived, and compared with those previously reported for the analogous normal human mammary cell subpopulations. The mouse and human epithelial subset signatures were then subjected to Ingenuity Pathway Analysis (IPA) to identify conserved pathways.

Results

The four mouse mammary cell subpopulations exhibited distinct gene signatures. Comparison of these signatures with the molecular profiles of different mouse models of mammary tumorigenesis revealed that tumors arising in MMTV-Wnt-1 and p53-/- mice were enriched for MaSC-subset genes, while the gene profiles of MMTV-Neu and MMTV-PyMT tumors were most concordant with the luminal progenitor cell signature. Comparison of the mouse mammary epithelial cell signatures with their human counterparts revealed substantial conservation of genes, while IPA highlighted a number of conserved pathways in the three epithelial subsets.

Conclusions

The conservation of genes and pathways across species further validates the use of the mouse as a model to study mammary gland development and highlights pathways that are likely to govern cell-fate decisions and differentiation. It is noteworthy that many of the conserved genes in the MaSC population have been considered as epithelial-mesenchymal transition (EMT) signature genes. Therefore, the expression of these genes in tumor cells may reflect basal epithelial cell characteristics and not necessarily cells that have undergone an EMT. Comparative analyses of normal mouse epithelial subsets with murine tumor models have implicated distinct cell types in contributing to tumorigenesis in different models.

B-cell-derived lymphotoxin promotes castration-resistant prostate cancer.

Searched Keywords: Stat3, IKK, Microenvironment, Inflammation, Cancer

Nature. 2010 Mar 11;464(7286):302-5.

Ammirante M, Luo JL, Grivennikov S, Nedospasov S, Karin M.

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA.

Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration-resistant metastatic carcinoma. Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent CaP, metastatic castration-resistant CaP is a major complication with high mortality. Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop castration-resistant CaP within 12-18 months. Despite extensive studies, the mechanisms underlying the emergence of castration-resistant CaP remain poorly understood and their elucidation is critical for developing improved therapies. Curiously, castration-resistant CaP remains androgen-receptor dependent, and potent androgen-receptor antagonists induce tumour regression in castrated mice. The role of inflammation in castration-resistant CaP has not been addressed, although it was reported that intrinsic NF-kappaB activation supports its growth. Inflammation is a localized protective reaction to injury or infection, but it also has a pathogenic role in many diseases, including cancer. Whereas acute inflammation is critical for host defence, chronic inflammation contributes to tumorigenesis and metastatic progression. The inflammation-responsive IkappaB kinase (IKK)-beta and its target NF-kappaB have important tumour-promoting functions within malignant cells and inflammatory cells. The latter, including macrophages and lymphocytes, are important elements of the tumour microenvironment, but the mechanisms underlying their recruitment remain obscure, although they are thought to depend on chemokine and cytokine production. We found that CaP progression is associated with inflammatory infiltration and activation of IKK-alpha, which stimulates metastasis by an NF-kappaB-independent, cell autonomous mechanism. Here we show that androgen ablation causes infiltration of regressing androgen-dependent tumours with leukocytes, including B cells, in which IKK-beta activation results in production of cytokines that activate IKK-alpha and STAT3 in CaP cells to enhance hormone-free survival.

Do scientists really need a PhD?

Young scientists at a Chinese genomics institute are foregoing conventional postgraduate training for the chance to be part of major scientific initiatives. Is this the way of the future?

nature Vol 464 | Issue no. 7285 | 4 March 2010

www.nature.com/nature/journal/v464/n7285/pdf/464007a.pdf

Method of the Year 2009, pluripotency

Nature Methods' Method of the Year 2009 goes to induced pluripotency for its potential for biological discovery. This series of articles—and the related video—showcase how induced pluripotency is coming into its own in 2009 as a tool for discovery in both basic and disease biology and explore the incredible impact this area promises to have in biological research.

January 2010, Volume 7 No 1 pp1-85

IAP Regulation of Metastasis

Cancer Cell, Volume 17, Issue 1, 53-64, 19 January 2010 | Copyright © 2010 Elsevier Inc. All rights reserved. | 10.1016/j.ccr.2009.11.021

Swarna Mehrotra, Lucia R. Languino, Christopher M. Raskett, Arthur M. Mercurio, Takehiko Dohi, Dario C. Altieri

* Highlights
* Inhibitor-of-Apoptosis (IAP) proteins mediate tumor cell invasion and metastasis
* This pathway requires NF-κB activation and is independent of IAP cytoprotection
* IAP tumor cell invasion involves signaling by fibronectin-β1 integrin and FAK, Src.

* Summary
* Inhibitor-of-Apoptosis (IAP) proteins contribute to tumor progression, but the requirements of this pathway are not understood. Here, we show that intermolecular cooperation between XIAP and survivin stimulates tumor cell invasion and promotes metastasis. This pathway is independent of IAP inhibition of cell death. Instead, a survivin-XIAP complex activates NF-κB, which in turn leads to increased fibronectin gene expression, signaling by β1 integrins, and activation of cell motility kinases FAK and Src. Therefore, IAPs are direct metastasis genes, and their antagonists could provide antimetastatic therapies in patients with cancer.

Journal stem cell work 'blocked'

By Pallab Ghosh Science correspondent, BBC News

Billions of pounds of public money is spent on stem cell research

Stem cell experts say they believe a small group of scientists is effectively vetoing high quality science from publication in journals.

In some cases they say it might be done to deliberately stifle research that is in competition with their own.

It has also emerged that 14 leading stem cell researchers have written an open letter to journal editors in order to highlight their dissatisfaction.

http://news.bbc.co.uk/2/hi/science/nature/8490291.stm

GAPDH

Novel roles for GAPDH in cell death and carcinogenesis.
Artículo

A selective eradication of human non-hereditary breast cancer cells by phenanthridine derived polyADP-ribose polymerase inhibitors

Dana Inbar-Rozensal email, Asher Castiel email, Leonid Visochek email, David Castel email, Francoise Dantzer email, Shai Izraeli email and Malka Cohen-Armon email

Breast Cancer Research 2009, 11:R78doi:10.1186/bcr2445
Published: 5 November 2009
Abstract (provisional)

Introduction

PARP-1 (polyADP-ribose polymerase-1) is known to be activated in response to DNA damage, and activated PARP-1 promotes DNA repair. However, a recently disclosed alternative mechanism of PARP-1 activation by phosphorylated externally regulated kinase (ERK) implicates PARP-1 in a vast number of signal transduction networks in the cell. Here, PARP-1 activation was examined for its possible effects on cell proliferation in both normal and malignant cells.
Methods

In-vitro (cell cultures) and in vivo (xenotransplants) experiments were performed.
Results

PARP inhibition by phenanthridine derived PARP inhibitors interfered with cell proliferation by causing G2/M arrest in both normal (human epithelial cells MCF10A and mouse embryonic fibroblasts) and human non-hereditary breast cancer cells MCF-7 and MDA231. However, while the normal cells were only transiently arrested, G2/M arrest in the malignant breast cancer cells was permanent and was accompanied by a massive cell death. In accordance, treatment with phenanthridine derived PARP inhibitor prevented the development of MCF-7 and MDA231 xenotransplants in female nude mice. Quiescent cells (neurons and cardiomyocytes) are not impaired by these PARP inhibitors.
Conclusions

p53 responsive elements in human retrotransposons

Oncogene (2009) 28, 3857–3865; doi:10.1038/onc.2009.246; published online 31 August 2009

C R Harris^1,2, A DeWan³, A Zupnick⁴, R Normart¹, A Gabriel⁵, C Prives⁴, A J Levine⁶ and J Hoh³

Long interspersed nuclear elements-1 (L1s) are highly repetitive DNA elements that are capable of altering the human genome through retrotransposition. To protect against L1 retroposition, the cell downregulates the expression of L1 proteins by various mechanisms, including high-density cytosine methylation of L1 promoters and DICER-dependent destruction of L1 mRNAs. In this report, a large number of p53 responsive elements, or p53 DNA binding sites, were detected in L1 elements within the human genome. At least some of these p53 responsive elements are functional and can act to increase the levels of L1 mRNA expression. The p53 protein can directly bind to a short 15-nucleotide sequence within the L1 promoter. This p53 responsive element within L1 is a recent addition to evolution, appearing 20 million years ago. This suggests an interplay between L1 elements, which have a rich history of causing changes in the genome, and the p53 protein, the function of which is to protect against genomic changes. To understand these observations, a model is proposed in which the increased expression of L1 mRNAs by p53 actually increases, rather than decreases, the genomic stability through amplification of p53-dependent processes for genomic protection.