Cette étude présente un modèle mathématique de régulation épigénétique permettant de rendre compte d'une augmentation de la variabilité de la méthylation de l'ADN et de l'expression des gènes dans le cancer

Regulated Noise in the Epigenetic Landscape of Development and Disease

Pujadas, Elisabet ; Feinberg, Andrew P

In this Perspective, we synthesize past and present observations in the field of epigenetics to propose a model in which the epigenome can modulate cellular plasticity in development and disease by regulating the effects of noise. In this model, the epigenome facilitates phase transitions in development and reprogramming and mediates canalization, or the ability to produce a consistent phenotypic outcome despite being challenged by variable conditions, during cell fate commitment. After [...]

Menée à l'aide d'un modèle murin, cette étude évalue l'intérêt de faire appel au système de transposon Sleeping Beauty pour identifier des mutations de gènes impliqués dans l'adénocarcinome du pancréas

Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

Mann, Karen M. ; Ward, Jerrold M. ; Yew, Christopher Chin Kuan ; Kovochich, Anne ; Dawson, David W. ; Black, Michael A. ; Brett, Benjamin T. ; Sheetz, Todd E. ; Dupuy, Adam J. ; Australian Pancreatic Cancer Genome Initiative ; Chang, David K. ; Biankin, Andrew V. ; Waddell, Nicola ; Kassahn, Karin S. ; Grimmond, Sean M. ; Rust, Alistair G. ; Adams, David J. ; Jenkins, Nancy A. ; Copeland, Neal G.

Pancreatic cancer is one of the most deadly cancers affecting the Western world. Because the disease is highly metastatic and difficult to diagnosis until late stages, the 5-y survival rate is around 5%. The identification of molecular cancer drivers is critical for furthering our understanding of the disease and development of improved diagnostic tools and therapeutics. We have conducted a mutagenic screen using Sleeping Beauty (SB) in mice to identify new candidate cancer genes in pancreatic [...]

Menée à l'aide d'un modèle murin et sur des échantillons tumoraux prélevés sur des patients atteints d'un lymphome diffus à grandes cellules B, d'un lymphome hodgkinien ou d'un d'un lymphome de Burkitt, cette étude montre que la protéine EBNA3B, encodée par le virus d'Epstein-Barr, joue un rôle de suppresseur de tumeurs dans ces lymphomes

EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors

White, Robert E. ; Rämer, Patrick C. ; Naresh, Kikkeri N. ; Meixlsperger, Sonja ; Pinaud, Laurie ; Rooney, Cliona ; Savoldo, Barbara ; Coutinho, Rita ; Bödör, Csaba ; Gribben, John ; Ibrahim, Hazem A. ; Bower, Mark ; Nourse, Jamie P. ; Gandhi, Maher K. ; Middeldorp, Jaap ; Cader, Fathima Z. ; Murray, Paul ; Münz, Christian ; Allday, Martin J.

Epstein-Barr virus (EBV) persistently infects more than 90% of the human population and is etiologically linked to several B cell malignancies, including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and diffuse large B cell lymphoma (DLBCL). Despite its growth transforming properties, most immune-competent individuals control EBV infection throughout their lives. EBV encodes various oncogenes, and of the 6 latency-associated EBV-encoded nuclear antigens, only EBNA3B is completely dispensable [...]

Menée sur un modèle murin, cette étude suggère que seuls les pneumocytes de type II sont susceptibles d'engendrer un adénocarcinome pulmonaire induit par l'activation de K-RAS

Evidence for type II cells as cells of origin of K-Ras–induced distal lung adenocarcinoma

Xu, Xia ; Rock, Jason R. ; Lu, Yun ; Futtner, Christopher ; Schwab, Brian ; Guinney, Justin ; Hogan, Brigid L. M. ; Onaitis, Mark W.

Identifying the cells of origin of lung cancer may lead to new therapeutic strategies. Previous work has focused upon the putative bronchoalveolar stem cell at the bronchioalveolar duct junction as a cancer cell of origin when a codon 12 K-Ras mutant is induced via adenoviral Cre inhalation. In the present study, we use two “knock-in” Cre-estrogen receptor alleles to inducibly express K-RasG12D in CC10+ epithelial cells and Sftpc+ type II alveolar cells of the adult mouse lung. Analysis of [...]

Cet article passe en revue les travaux récents sur le rôle des cellules souches du cancer dans le processus métastatique

Cancer stem cells and metastasis

Sampieri, Katia ; Fodde, Riccardo

Cancer stem cells (CSCs) represent a subpopulation of tumour cells endowed with self-renewal and multi-lineage differentiation capacity but also with an innate resistance to cytotoxic agents, a feature likely to pose major clinical challenges towards the complete eradication of minimal residual disease in cancer patients. Operationally, CSCs are defined by their tumour-propagating ability when serially transplanted into immune-compromised mice and by their capacity to fully recapitulate the [...]

Cet article passe en revue les travaux récents sur les différents rôles attribués aux cellules immunitaires infiltrantes dans la progression tumorale

The immune contexture in human tumours: impact on clinical outcome

Fridman, Wolf Herman ; Pagès, Franck ; Sautès-Fridman, Catherine ; Galon, Jérôme

Tumours grow within an intricate network of epithelial cells, vascular and lymphatic vessels, cytokines and chemokines, and infiltrating immune cells. Different types of infiltrating immune cells have different effects on tumour progression, which can vary according to cancer type. In this Opinion article we discuss how the context-specific nature of infiltrating immune cells can affect the prognosis of patients.

Cet article passe en revue les travaux récents sur les mécanismes impliquant les neutrophiles associés aux tumeurs dans la biologie du cancer

Tumor Associated Neutrophils: Friend or Foe?

Fridlender, Zvi G. ; Albelda, Steven M.

Neutrophils play an established role in host defense and in killing invading microorganisms. Although neutrophils are traditionally considered in the context of their anti-bacterial functions, it is becoming increasingly clear that tumor-associated neutrophils (TAN) play a major role in cancer biology. Neutrophils make up a significant portion of the inflammatory cell infiltrate in many models of cancer. Like all other leukocytes, they move into tissues under the influence of specific [...]

Menée in vivo, cette étude met en évidence un mécanisme de régulation différentielle des récepteurs VEGFR2 et VEGFR3, impliqués dans l'angiogenèse, par la protéine Notch

Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling

Benedito, Rui ; Rocha, Susana F. ; Woeste, Marina ; Zamykal, Martin ; Radtke, Freddy ; Casanovas, Oriol ; Duarte, Antonio ; Pytowski, Bronislaw ; Adams, Ralf H.

Developing tissues and growing tumours produce vascular endothelial growth factors (VEGFs), leading to the activation of the corresponding receptors in endothelial cells. The resultant angiogenic expansion of the local vasculature can promote physiological and pathological growth processes. Previous work has uncovered that the VEGF and Notch pathways are tightly linked. Signalling triggered by VEGF-A (also known as VEGF) has been shown to induce expression of the Notch ligand DLL4 in angiogenic [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par l'expression du variant III du récepteur du facteur de croissance épidermique dans les cellules souches de cancer du sein

Epidermal Growth Factor Receptor Variant III Contributes to Cancer Stem Cell Phenotypes in Invasive Breast Carcinoma

Del Vecchio, Catherine A ; Jensen, Kristin C. ; Nitta, Ryan T ; Shain, A Hunter ; Giacomini, Craig P ; Wong, Albert J

EGFRvIII is a tumor-specific variant of the epidermal growth factor receptor (EGFR). Although EGFRvIII is most commonly found in glioblastoma, its expression in other tumor types remains controversial. In this study, we investigated EGFRvIII expression and amplification in primary breast carcinoma. Our analyses confirmed the presence of EGFRvIII, but in the absence of amplification or rearrangement of the EGFR locus. Nested RT-PCR and flow cytometry were used to detect a higher percentage of [...]

Cet article passe en revue les travaux récents sur le rôle des anomalies du métabolisme cellulaire dans les maladies humaines, notamment le cancer

Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us?

DeBerardinis, Ralph J ; Thompson, Craig B

An understanding of metabolic pathways based solely on biochemistry textbooks would underestimate the pervasive role of metabolism in essentially every aspect of biology. It is evident from recent work that many human diseases involve abnormal metabolic states often genetically programmed that perturb normal physiology and lead to severe tissue dysfunction. Understanding these metabolic outliers is now a crucial frontier in disease-oriented research. This Review discusses the broad impact of [...]

Cet article passe en revue l'apport des modèles animaux à la compréhension de l'adénocarcinome canalaire du pancréas et au développement de nouvelles approches pour le diagnostic et le traitement de la maladie

What We Have Learned About Pancreatic Cancer from Mouse Models

Perez-Mancera, Pedro A. ; Guerra, Carmen ; Barbacid, Mariano ; Tuveson, David A.

Pancreatic ductal adenocarcinoma (PDA) is one of the most devastating malignancies worldwide. A total of 43,140 new cases (ranked 10th) and 36,800 deaths (ranked 4th) from pancreatic cancer were estimated to occur in the United States during 2010, with an overall 5-year survival rate of just 6%1. This dire clinical situation exists despite the recent advances in our understanding of the genetics and biology of PDA. Most patients with advanced PDA either do not respond, or respond only [...]