A partir d'échantillons tumoraux et sanguins prélevés sur des patients atteints d'un lymphome T angio-immunoblastique, puis menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par une mutation R172K du gène IDH2 dans le développement de la maladie

The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development

Lemonnier, François ; Cairns, Rob A. ; Inoue, Satoshi ; Li, Wanda Y. ; Dupuy, Aurélie ; Broutin, Sophie ; Martin, Nadine ; Fataccioli, Virginie ; Pelletier, Romain ; Wakeham, Andrew ; Snow, Bryan E. ; de Leval, Laurence ; Pujals, Anais ; Haioun, Corinne ; Paci, Angelo ; Tobin, Erica R. ; Narayanaswamy, Rohini ; Yen, Katherine ; Jin, Shengfang ; Gaulard, Philippe ; Mak, Tak W.

Oncogenic isocitrate dehydrogenase (IDH)1 and IDH2 mutations at three hotspot arginine residues cause an enzymatic gain of function that leads to the production and accumulation of the metabolite 2-hydroxyglutarate (2HG), which contributes to the development of a number of malignancies. In the hematopoietic system, mutations in IDH1 at arginine (R) 132 and in IDH2 at R140 and R172 are commonly observed in acute myeloid leukemia, and elevated 2HG is observed in cells and serum. However, in [...]

Menée à l'aide d'une technique de séquençage du génome entier sur des échantillons de tumeur primitive et de plusieurs métastases prélevés sur deux patientes atteintes d'un cancer du sein "basal-like" triplement négatif, cette étude met en évidence l'évolution des mutations et du nombre de copies de gènes entre l'ADN de la tumeur primitive et l'ADN des métastases

Tumor Evolution in Two Patients with Basal-like Breast Cancer: A Retrospective Genomics Study of Multiple Metastases

Hoadley, Katherine A. ; Siegel, Marni B. ; Kanchi, Krishna L. ; Miller, Christopher A. ; Ding, Li ; Zhao, Wei ; He, Xiaping ; Parker, Joel S. ; Wendl, Michael C. ; Fulton, Robert S. ; Demeter, Ryan T. ; Wilson, Richard K. ; Carey, Lisa A. ; Perou, Charles M. ; Mardis, Elaine R.

Background : Metastasis is the main cause of cancer patient deaths and remains a poorly characterized process. It is still unclear when in tumor progression the ability to metastasize arises and whether this ability is inherent to the primary tumor or is acquired well after primary tumor formation. Next-generation sequencing and analytical methods to define clonal heterogeneity provide a means for identifying genetic events and the temporal relationships between these events in the primary and [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels une phosphorylation de la protéine Mdm2 régule la fonction de suppression de tumeurs exercée par le facteur de transcription p53

Phosphorylation of the Mdm2 oncoprotein by the c-Abl tyrosine kinase regulates p53 tumor suppression and the radiosensitivity of mice

Carr, Michael I. ; Roderick, Justine E. ; Zhang, Hong ; Woda, Bruce A. ; Kelliher, Michelle A. ; Jones, Stephen N.

The p53 tumor suppressor acts as a guardian of the genome by preventing the propagation of DNA damage-induced breaks and mutations to subsequent generations of cells. We have previously shown that phosphorylation of the Mdm2 oncoprotein at Ser394 by the ATM kinase is required for robust p53 stabilization and activation in cells treated with ionizing radiation, and that loss of Mdm2 Ser394 phosphorylation leads to spontaneous tumorigenesis and radioresistance in Mdm2S394A mice. Previous in vitro [...]

Cet article passe en revue les travaux récents sur le rôle de l'autophagie dans la transformation de cellules souches hématopoïétiques normales en cellules leucémiques

Autophagy, a key mechanism of oncogenesis and resistance in leukemia

Auberger, Patrick ; Puissant, Alexandre

Autophagy is a lysosomal pathway involved in degradation of intracellular material. It appears as an adaptation mechanism that is essential for cellular homeostasis in response to various stress conditions. Over the past decade, many studies have linked alteration of autophagy with cancer initiation and progression, autoimmune, inflammatory, metabolic, and degenerative diseases. This review highlights recent findings on the impact of autophagy on leukemic transformation of normal hematopoietic [...]

A partir d'échantillons tumoraux prélevés sur 283 patients atteints d'un mélanome, puis menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le gène PPP2R3B, situé sur le chromosome X, exerce une fonction de suppresseur de tumeurs

The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene

van Kempen, Léon C. L. ; Redpath, Margaret ; Elchebly, Mounib ; Klein, Kathleen Oros ; Papadakis, Andreas I. ; Wilmott, James S. ; Scolyer, Richard A. ; Edqvist, Per-Henrik ; Pontén, Fredrik ; Schadendorf, Dirk ; van Rijk, Anke F. ; Michiels, Stefan ; Dumay, Anne ; Helbling-Leclerc, Anne ; Dessen, Philippe ; Wouters, Jasper ; Stass, Marguerite ; Greenwood, Celia M. T. ; Ghanem, Ghanem E. ; van den Oord, Joost ; Feunteun, Jean ; Spatz, Alan

A new X-linked tumor suppressor gene that escapes X inactivation drives higher expression of its encoded protein PR70—the regulatory subunit of protein phosphatase 2A—in females and might explain the worse prognoses observed in men with melanoma, relative to women. The authors showed that in melanoma, the most serious type of skin cancer, loss of an inactivated X chromosome from females was strongly associated with poor distant metastasis–free survival, an observation that suggests a dosage [...]

Menée in vitro et in vivo sur des modèles de cancer de l'ovaire, cette étude met en évidence des mécanismes par lesquels, via des exosomes, des cellules cancéreuses secrètent en abondance un micro-ARN connu pour exercer une fonction de suppresseur de tumeurs (miR-6126)

Ubiquitous Release of Exosomal Tumor Suppressor miR-6126 from Ovarian Cancer Cells

Kanlikilicer, Pinar ; Rashed, Mohammed H. ; Bayraktar, Recep ; Mitra, Rahul ; Ivan, Cristina ; Aslan, Burcu ; Zhang, Xinna ; Filant, Justyna ; Silva, Andreia M. ; Rodriguez-Aguayo, Cristian ; Bayraktar, Emine ; Pichler, Martin ; Ozpolat, Bulent ; Calin, George A. ; Sood, Anil K. ; Lopez-Berestein, Gabriel

Cancer cells actively promote their tumorigenic behavior by reprogramming gene expression. Loading intraluminal vesicles with specific miRNAs and releasing them into the tumor microenvironment as exosomes is one mechanism of reprogramming whose regulation remains to be elucidated. Here, we report that miR-6126 is ubiquitously released in high abundance from both chemosensitive and chemoresistant ovarian cancer cells via exosomes. Overexpression of miR-6126 was confirmed in healthy ovarian [...]

Menée à l'aide de modèles murins de cancer colorectal, cette étude met en évidence des mécanismes par lesquels, en régulant les voies de signalisation mTOR, la protéine NLRC3 exerce une fonction de suppresseur de tumeurs

NLRC3 is an inhibitory sensor of PI3K–mTOR pathways in cancer

Karki, Rajendra ; Man, Si Ming ; Malireddi, R. K. Subbarao ; Kesavardhana, Sannula ; Zhu, Qifan ; Burton, Amanda R. ; Sharma, Bhesh Raj ; Qi, Xiaopeng ; Pelletier, Stephane ; Vogel, Peter ; Rosenstiel, Philip ; Kanneganti, Thirumala-Devi

NLRs (nucleotide-binding domain and leucine-rich repeats) belong to a large family of cytoplasmic sensors that regulate an extraordinarily diverse range of biological functions. One of these functions is to contribute to immunity against infectious diseases, but dysregulation of their functional activity leads to the development of inflammatory and autoimmune diseases. Cytoplasmic innate immune sensors, including NLRs, are central regulators of intestinal homeostasis. NLRC3 (also known as [...]

Menée sur des lignées cellulaires de carcinomes humains, cette étude met en évidence des mécanismes par lesquels, en perdant des chromosomes porteurs de gènes codant pour des protéines de jonctions intercellulaires, des cellules épithéliales acquièrent un phénotype mésenchymateux invasif

Chromosome instability drives phenotypic switching to metastasis

Gao, ChongFeng ; Su, Yanli ; Koeman, Julie ; Haak, Elizabeth ; Dykema, Karl ; Essenberg, Curt ; Hudson, Eric ; Petillo, David ; Khoo, Sok Kean ; Vande Woude, George F.

Chromosome instability (CIN) is the most striking feature of human cancers. However, how CIN drives tumor progression to metastasis remains elusive. Here we studied the role of chromosome content changes in generating the phenotypic dynamics that are required for metastasis. We isolated epithelial and mesenchymal clones from human carcinoma cell lines and showed that the epithelial clones were able to generate mesenchymal variants, which had the potential to further produce epithelial [...]

Cet article passe en revue les travaux récents sur le rôle des inhibiteurs physiologiques des métalloprotéases matricielles dans la progression tumorale

TIMPs: versatile extracellular regulators in cancer

Jackson, Hartland W. ; Defamie, Virginie ; Waterhouse, Paul ; Khokha, Rama

A compelling long-term goal of cancer biology is to understand the crucial players during tumorigenesis in order to develop new interventions. Here, we review how the four non-redundant tissue inhibitors of metalloproteinases (TIMPs) regulate the pericellular proteolysis of a vast range of matrix and cell surface proteins, generating simultaneous effects on tumour architecture and cell signalling. Experimental studies demonstrate the contribution of TIMPs to the majority of cancer hallmarks, [...]

Menée notamment à l'aide d'un modèle murin de cancer métastatique, cette étude met en évidence des mécanismes par lesquels, via l'expression d'une enzyme dans le réticulum endoplasmique, un gène p53 muté favorise le processus métastatique

Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5

Vogiatzi, Fotini ; Brandt, Dominique T. ; Schneikert, Jean ; Fuchs, Jeannette ; Grikscheit, Katharina ; Wanzel, Michael ; Pavlakis, Evangelos ; Charles, Joël P. ; Timofeev, Oleg ; Nist, Andrea ; Mernberger, Marco ; Kantelhardt, Eva J. ; Siebolts, Udo ; Bartel, Frank ; Jacob, Ralf ; Rath, Ariane ; Moll, Roland ; Grosse, Robert ; Stiewe, Thorsten

Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate [...]

Menée à l'aide de divers modèles murins de cancer de la prostate, cette étude met en évidence des mécanismes par lesquels la perte d'expression du gène RB favorise le processus métastatique

RB loss promotes prostate cancer metastasis

Thangavel, Chellappagounder ; Boopathi, Ettickan ; Liu, Yi ; Haber, Alex ; Ertel, Adam ; Bhardwaj, Anshul ; Addya, Sankar ; Williams, Noelle ; Ciment, Steve ; Cotzia, Paolo ; Dean, Jeffry L. ; Snook, Adam E. ; McNair, Chris ; Price, Matthew A. ; Hernandez, James R. ; Zhao, Shuang G. ; Birbe, Ruth ; McCarthy, James B. ; Turely, Eva A. ; Pienta, Kenneth J. ; Feng, Felix Y. ; Dicker, Adam P. ; Knudsen, Karen E. ; Den, Robert B.

RB loss occurs commonly in neoplasia but its contributions to advanced cancer have not been assessed directly. Here we show that RB loss in multiple murine models of cancer produces a pro-metastatic phenotype. Gene expression analyses showed that regulation of the cell motility receptor RHAMM by the RB/E2F pathway was critical for epithelia-mesenchyme translation, motility and invasion by cancer cells. Genetic modulation or pharmacological inhibition of RHAMM activity was sufficient and [...]

Cet article passe en revue les travaux récents sur le rôle du mosaïcisme dans le développement des pathologies et, en particulier, analyse les conséquences de ces travaux sur les performances des tests génétiques en médecine

Mosaicism in health and disease - clones picking up speed

Forsberg, Lars A. ; Gisselsson, David ; Dumanski, Jan P.

Post-zygotic variation refers to genetic changes that arise in the soma of an individual and that are not usually inherited by the next generation. Although there is a paucity of research on such variation, emerging studies show that it is common: individuals are complex mosaics of genetically distinct cells, to such an extent that no two somatic cells are likely to have the exact same genome. Although most types of mutation can be involved in post-zygotic variation, structural genetic variants [...]

Cet article présente une base de données sur la méthylation de l'ADN dans les lignées cellulaires cancéreuses NCI-60

The NCI-60 Methylome and its Integration into CellMiner

Reinhold, William C. ; Varma, Sudhir ; Sunshine, Margot ; Rajapakse, Vinodh ; Luna, Augustin ; Kohn, Kurt W. ; Stevenson, Holly ; Wang, Yonghong ; Heyn, Holger ; Nogales, Vanesa ; Moran, Sebastian ; Goldstein, David J. ; Doroshow, James H. ; Meltzer, Paul S. ; Esteller, Manel ; Pommier, Yves

A unique resource for systems pharmacology and genomic studies is the NCI-60 cancer cell line panel, which provides data for the largest publicly available library of compounds with cytotoxic activity (~21,000 compounds), including 108 FDA-approved and 70 clinical trial drugs as well as genomic data, including whole-exome sequencing, gene and microRNA transcripts, DNA copy number, and protein levels. Here we provide the first readily usable genome-wide DNA methylation database for the NCI-60, [...]