Distant metastasis occurs late during the genetic evolution of pancreatic cancer.

Nature. 2010 Oct 28;467(7319):1114-7.
Distant metastasis occurs late during the genetic evolution of pancreatic cancer.
Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, Kamiyama M, Hruban RH, Eshleman JR, Nowak MA, Velculescu VE, Kinzler KW, Vogelstein B, Iacobuzio-Donahue CA.

Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
Comment in:

Nature. 2010 Oct 28;467(7319):1053-5.
Abstract
Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.

DNA damage-mediated induction of a chemoresistant niche.

Cell. 2010 Oct 29;143(3):355-66.
DNA damage-mediated induction of a chemoresistant niche.
Gilbert LA, Hemann MT.

The Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract
While numerous cell-intrinsic processes are known to play decisive roles in chemotherapeutic response, relatively little is known about the impact of the tumor microenvironment on therapeutic outcome. Here, we use a well-established mouse model of Burkitt's lymphoma to show that paracrine factors in the tumor microenvironment modulate lymphoma cell survival following the administration of genotoxic chemotherapy. Specifically, IL-6 and Timp-1 are released in the thymus in response to DNA damage, creating a "chemo-resistant niche" that promotes the survival of a minimal residual tumor burden and serves as a reservoir for eventual tumor relapse. Notably, IL-6 is released acutely from thymic endothelial cells in a p38-dependent manner following genotoxic stress, and this acute secretory response precedes the gradual induction of senescence in tumor-associated stromal cells. Thus, conventional chemotherapies can induce tumor regression while simultaneously eliciting stress responses that protect subsets of tumor cells in select anatomical locations from drug action. PAPERFLICK:

TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs.

Nature. 2010 Oct 21;467(7318):986-90.
TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs.
Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL, Leung ML, El-Naggar A, Creighton CJ, Suraokar MB, Wistuba I, Flores ER.

Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Abstract
Aberrant expression of microRNAs (miRNAs) and the enzymes that control their processing have been reported in multiple biological processes including primary and metastatic tumours, but the mechanisms governing this are not clearly understood. Here we show that TAp63, a p53 family member, suppresses tumorigenesis and metastasis, and coordinately regulates Dicer and miR-130b to suppress metastasis. Metastatic mouse and human tumours deficient in TAp63 express Dicer at very low levels, and we found that modulation of expression of Dicer and miR-130b markedly affected the metastatic potential of cells lacking TAp63. TAp63 binds to and transactivates the Dicer promoter, demonstrating direct transcriptional regulation of Dicer by TAp63. These data provide a novel understanding of the roles of TAp63 in tumour and metastasis suppression through the coordinate transcriptional regulation of Dicer and miR-130b and may have implications for the many processes regulated by miRNAs.

O(2) regulates stem cells through Wnt/β-catenin signalling.

Nat Cell Biol. 2010 Sep 19. [Epub ahead of print]
O(2) regulates stem cells through Wnt/β-catenin signalling.
Mazumdar J, O'Brien WT, Johnson RS, Lamanna JC, Chavez JC, Klein PS, Simon MC.
[1] Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. [2] Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. [3] Current address: Clinical Biomarkers, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.
Abstract
Stem cells reside in specialized microenvironments or 'niches' that regulate their function. In vitro studies using hypoxic culture conditions (< 5% O(2)) have revealed strong regulatory links between O(2) availability and functions of stem and precursor cells. Although some stem cells are perivascular, others may occupy hypoxic niches and be regulated by O(2) gradients. However, the underlying mechanisms remain unclear. Here, we show that hypoxia inducible factor-1α (HIF-1α), a principal mediator of hypoxic adaptations, modulates Wnt/β-catenin signalling in hypoxic embryonic stem (ES) cells by enhancing β-catenin activation and expression of the downstream effectors LEF-1 and TCF-1. This regulation extends to primary cells, including isolated neural stem cells (NSCs), and is not observed in differentiated cells. In vivo, Wnt/β-catenin activity is closely associated with low O(2) regions in the subgranular zone of the hippocampus, a key NSC niche. Hif-1α deletion impairs hippocampal Wnt-dependent processes, including NSC proliferation, differentiation and neuronal maturation. This decline correlates with reduced Wnt/β-catenin signalling in the subgranular zone. O(2) availability, therefore, may have a direct role in stem cell regulation through HIF-1α modulation of Wnt/β-catenin signalling.

Reactive Astrocytes Protect Melanoma Cells from Chemotherapy by Sequestering Intracellular Calcium through Gap Junction Communication Channels.

Neoplasia. 2010 Sep;12(9):748-54.

Lin Q, Balasubramanian K, Fan D, Kim SJ, Guo L, Wang H, Bar-Eli M, Aldape KD, Fidler IJ.

Brain metastases are highly resistant to chemotherapy. Metastatic tumor cells are known to exploit the host microenvironment for their growth and survival. We report here that melanoma brain metastases are surrounded and infiltrated by activated astrocytes, and we hypothesized that these astrocytes can play a role similar to their established ability to protect neurons from apoptosis. In coculture experiments, astrocytes, but not fibroblasts, reduced apoptosis in human melanoma cells treated with various chemotherapeutic drugs. This chemoprotective effect was dependent on physical contact and gap junctional communication between astrocytes and tumor cells. Moreover, the protective effect of astrocytes resulted from their sequestering calcium from the cytoplasm of tumor cells. These data suggest that brain tumors can, in principle, harness the neuroprotective effects of reactive astrocytes for their own survival and implicate a heretofore unrecognized mechanism for resistance in brain metastasis that might be of relevance in the clinic.

Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer

Aleix Prat , Joel S Parker , Olga Karginova , Cheng Fan , Chad Livasy , Jason I Herschkowitz , Xiaping He and Charles M Perou

Breast Cancer Research 2010, 12:R68doi:10.1186/bcr2635

Published:	2 September 2010

Abstract (provisional)

Introduction

In breast cancer, gene expression analyses have defined five tumor subtypes (luminal A, luminal B, HER2-enriched, basal-like and claudin-low), each of which has unique biologic and prognostic features. Here, we comprehensively characterize the recently identified claudin-low tumor subtype.

Methods

The clinical, pathological and biological features of claudin-low tumors were compared to the other tumor subtypes using an updated human tumor database and multiple independent data sets. These main features of claudin-low tumors were also evaluated in a panel of breast cancer cell lines and genetically engineered mouse models.

Results

Claudin-low tumors are characterized by the low to absent expression of luminal differentiation markers, high enrichment for epithelial-to-mesenchymal transition markers, immune response genes and cancer stem cell-like features. Clinically, the majority of claudin-low tumors are poor prognosis estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and epidermal growth factor receptor 2 (HER2)-negative (triple negative) invasive ductal carcinomas with a high frequency of metaplastic and medullary differentiation. They also have a response rate to standard preoperative chemotherapy that is intermediate between that of basal-like and luminal tumors. Interestingly, we show that a group of highly utilized breast cancer cell lines, and several genetically engineered mouse models, express the claudin-low phenotype. Finally, we confirm that a prognostically relevant differentiation hierarchy exists across all breast cancers in which the claudin-low subtype most closely resembles the mammary epithelial stem cell.

Conclusions

These results should help to improve our understanding of the biologic heterogeneity of breast cancer and provide tools for the further evaluation of the unique biology of claudin-low tumors and cell lines.

Stem cells

Hola, les anexo el link de un artículo de revisión de stem cells.

Understanding the cancer stem cell

http://www.biotechniques.com/news/biotechniquesNews/biotechniques-301169.html

Next generation sorting: FRET adapted for high throughput stem cell sorting
08/12/2010 Andrew S. Wiecek
A FRET-based method to purify stem cell cultures paves the way for the next generation of cell sorting.

Seria muy interesante para el estudio de celulas troncales de cancer.

http://www.biotechniques.com/news/biotechniquesNews/biotechniques-301169.html

No todo en Sudáfrica es fútbol

Investigadores sostienen que un gel bajo prueba en Sudáfrica disminuyó de forma sustancial el riesgo de infección de VIH-SIDA entre mujeres que lo utilizaron consistentemente antes de tener relaciones sexuales.

Un estudio dado a conocer este lunes 19 de julio, por el Centro para el Programa de Investigación del SIDA de Sudáfrica (CAPRISA) indica que el gel microbicida basado en el fármaco tenofovir redujo la tasa de infección de VIH en un 39% en un grupo de casi 900 voluntarias a lo largo de dos años y medio.

La investigación presentada en la XVIII Conferencia internacional sobre el SIDA en Viena también constató que el gel redujo en un 51% la tasa de infección del herpes simplex virus-2.

La Organización Mundial de la Salud (OMS) y ONUSIDA calificaron la noticia como un avance revolucionario.

http://www.sciencemag.org/cgi/rapidpdf/science.1193748.pdf

Correciones y nuevos blancos...

The most important issue when trying to find mutations that cause disease via DNA sequencing is to keep the sequencing error rate as low as possible.

Whole-genome sequencing of DNA from two children with Mendelian disorders and from their healthy parents allows efficient correction of sequencing errors and the identification of causal genes.

Nature Methods 7, 350 (2010)
doi:10.1038/nmeth0510-350

http://www.nature.com/nmeth/journal/v7/n5/full/nmeth0510-350.html

Creación de una célula bacteriana controlada por un genoma sintetizado químicamente.

Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome
Craig Venter

We report the design, synthesis and assembly of the 1.08-
Mbp Mycoplasma mycoides JCVI-syn1.0 genome starting
from digitized genome sequence information and its
transplantation into a Mycoplasma capricolum recipient
cell to create new Mycoplasma mycoides cells that are
controlled only by the synthetic chromosome. The only
DNA in the cells is the designed synthetic DNA sequence,
including “watermark” sequences and other designed
gene deletions and polymorphisms, and mutations
acquired during the building process. The new cells have
expected phenotypic properties and are capable of
continuous self-replication.

RNAs en todos lados.

A series of reports over the last few years have indicated that a much larger portion of the mammalian genome is transcribed than can be accounted for by currently annotated genes, but the quantity and nature of these additional transcripts remains unclear. Here, we have used data from single- and paired-end RNA-Seq and tiling arrays to assess the quantity and composition of transcripts in PolyA+ RNA from human and mouse tissues. Relative to tiling arrays, RNA-Seq identifies many fewer transcribed regions (“seqfrags”) outside known exons and ncRNAs. Most nonexonic seqfrags are in introns, raising the possibility that they are fragments of pre-mRNAs. The chromosomal locations of the majority of intergenic seqfrags in RNA-Seq data are near known genes, consistent with alternative cleavage and polyadenylation site usage, promoter- and terminator-associated transcripts, or new alternative exons; indeed, reads that bridge splice sites identified 4,544 new exons, affecting 3,554 genes. Most of the remaining seqfrags correspond to either single reads that display characteristics of random sampling from a low-level background or several thousand small transcripts (median length = 111 bp) present at higher levels, which also tend to display sequence conservation and originate from regions with open chromatin. We conclude that, while there are bona fide new intergenic transcripts, their number and abundance is generally low in comparison to known exons, and the genome is not as pervasively transcribed as previously reported.

Citation: van Bakel H, Nislow C, Blencowe BJ, Hughes TR (2010) Most “Dark Matter” Transcripts Are Associated With Known Genes. PLoS Biol 8(5): e1000371. doi:10.1371/journal.pbio.1000371