Menée sur des échantillons prélevés sur 89 patients pédiatriques et 122 patients adultes atteints d'une leucémie aiguë lymphoblastique T, cettte étude de séquençage des exons identifie de fréquentes mutations des gènes RPL5 et PRL10 chez les enfants et du gène CNOT3 chez les adultes

Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia

De Keersmaecker, Kim ; Atak, Zeynep Kalender ; Li, Ning ; Vicente, Carmen ; Patchett, Stephanie ; Girardi, Tiziana ; Gianfelici, Valentina ; Geerdens, Ellen ; Clappier, Emmanuelle ; Porcu, Michaël ; Lahortiga, Idoya ; Luca, Rossella ; Yan, Jiekun ; Hulselmans, Gert ; Vranckx, Hilde ; Vandepoel, Roel ; Sweron, Bram ; Jacobs, Kris ; Mentens, Nicole ; Wlodarska, Iwona ; Cauwelier, Barbara ; Cloos, Jacqueline ; Soulier, Jean ; Uyttebroeck, Anne ; Bagni, Claudia ; Hassan, Bassem A. ; Vandenberghe, Peter ; Johnson, Arlen W. ; Aerts, Stein ; Cools, Jan

T-cell acute lymphoblastic leukemia (T-ALL) is caused by the cooperation of multiple oncogenic lesions. We used exome sequencing on 67 T-ALLs to gain insight into the mutational spectrum in these leukemias. We detected protein-altering mutations in 508 genes, with an average of 8.2 mutations in pediatric and 21.0 mutations in adult T-ALL. Using stringent filtering, we predict seven new oncogenic driver genes in T-ALL. We identify CNOT3 as a tumor suppressor mutated in 7 of 89 (7.9%) adult [...]

Menée à partir d'échantillons prélevés sur 20 patients ayant été atteints d'un mélanome métastatique, cette étude identifie la présence du phénomène de chromothripsis (réarrangements génomiques massifs) chez les patients dont la durée de survie était la plus faible

Chromothripsis and focal copy number alterations determine poor outcome in malignant melanoma

Hirsch, Daniela ; Kemmerling, Ralf ; Davis, Sean ; Camps, Jordi ; Meltzer, Paul S ; Ried, Thomas ; Gaiser, Timo

Genetic changes during tumorigenesis are usually acquired sequentially. However, a recent study showed that in 2 to 3% of all cancers a single catastrophic event, termed chromothripsis, can lead to massive genomic rearrangements confined to one or a few chromosomes. In order to explore whether the degree of genomic instability and chromothripsis influences prognosis in cancer, we retrospectively applied array comparative genomic hybridization (aCGH) to 20 malignant melanomas (MM) that showed, [...]

Menée sur des échantillons prélevés sur des patients atteints d'un cancer de la prostate, y compris des cancers résistant à la castration, cette étude identifie un groupe de gènes dont l'expression est régulée par le récepteur des androgènes

The Androgen Receptor Induces a Distinct Transcriptional Program in Castration-Resistant Prostate Cancer in Man

Sharma, Naomi L ; Massie, Charlie E ; Ramos-Montoya, Antonio ; Zecchini, Vincent ; Scott, Helen E ; Lamb, Alastair D ; MacArthur, Stewart ; Stark, Rory ; Warren, Anne Y ; Mills, Ian G ; Neal, David E

The androgen receptor (AR) regulates prostate cell growth in man, and prostate cancer is the commonest cancer in men in the UK. We present a comprehensive analysis of AR binding sites in human prostate cancer tissues, including castrate-resistant prostate cancer (CRPC). We identified thousands of AR binding sites in CRPC tissue, most of which were not identified in PC cell lines. Many adjacent genes showed AR regulation in xenografts but not in cultured LNCaPs, demonstrating an [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel l'activation d'une voie de signalisation inflammatoire dans le micro-environnement tumoral induit une dédifférenciation de cellules du côlon qui, ainsi, acquièrent des capacités de cellules souches cancéreuses

Intestinal Tumorigenesis Initiated by Dedifferentiation and Acquisition of Stem-Cell-like Properties

Schwitalla, Sarah ; Fingerle, Alexander A ; Cammareri, Patrizia ; Nebelsiek, Tim ; Göktuna, Serkan I ; Ziegler, Paul K ; Canli, Ozge ; Heijmans, Jarom ; Huels, David J ; Moreaux, Guenievre ; Rupec, Rudolf A ; Gerhard, Markus ; Schmid, Roland ; Barker, Nick ; Clevers, Hans ; Lang, Roland ; Neumann, Jens ; Kirchner, Thomas ; Taketo, Makoto M ; van den Brink, Gijs R ; Sansom, Owen J ; Arkan, Melek C ; Greten, Florian R

Cell-type plasticity within a tumor has recently been suggested to cause a bidirectional conversion between tumor-initiating stem cells and nonstem cells triggered by an inflammatory stroma. NF-

Menée in vitro et à l'aide de xénogreffes, cette étude montre que, selon l'expression du récepteur ER-alpha, les cellules souches de cancer du sein répondent différemment à une hypoxie

Contrasting hypoxic effects on breast cancer stem cell hierarchy is dependent on ERα status

Harrison, Hannah ; Rogerson, Lynsey ; Gregson, Hannah J ; Brennan, Keith R. ; Clarke, Robert B. ; Landberg, Göran

Tumor hypoxia is often linked to decreased survival in breast cancer patients and current therapeutic strategies aim to target the hypoxic response. One way in which this is done is by blocking hypoxia induced angiogenesis. Anti-angiogenic therapies show some therapeutic potential with increased disease free survival but these initial promising results are short lived and followed by tumor progression. We hypothesized that this may be due to altered cancer stem cell (CSC) activity resulting [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels l'enzyme FUT8 favorise la progression tumorale et le processus métastatique dans le cancer du poumon non à petites cellules

Fucosyltransferase 8 as a functional regulator of nonsmall cell lung cancer

Chen, Chien-Yu ; Jan, Yi-Hua ; Juan, Yi-Hsiu ; Yang, Chih-Jen ; Huang, Ming-Shyan ; Yu, Chong-Jen ; Yang, Pan-Chyr ; Hsiao, Michael ; Hsu, Tsui-Ling ; Wong, Chi-Huey

The up-regulation of fucosyltransferase 8 (FUT8), the only enzyme catalyzing α1,6-fucosylation in mammals, has been observed in several malignant cancers including liver, ovarian, thyroid, and colorectal cancers. However, the pathological role and the regulatory mechanism of FUT8 in cancers remain largely unknown. In the current study, we report that the expression of FUT8 is up-regulated in nonsmall cell lung cancer (NSCLC) and correlates with tumor metastasis, disease recurrence, and poor [...]

Menée à l'aide de modèles murins génétiquement modifés, cette étude met en évidence un mécanisme par lequel la protéine exprimée par un gène N-Ras muté favorise, dans un contexte inflammatoire, la tumorigenèse d'un cancer colorectal

Mutant N-Ras protects colorectal cancer cells from stress-induced apoptosis and contributes to cancer development and progression

Wang, Yufang ; Velho, Sergia ; Vakiani, Efsevia ; Peng, Shouyong ; Bass, Adam J. ; Chu, Gerald C ; Gierut, Jessica ; Bugni, James M ; Der, Channing J. ; Philips, Mark ; Solit, David B ; Haigis, Kevin M.

N-Ras is one member of a family of oncoproteins that are commonly mutated in cancer. Activating mutations in N-Ras occur in a subset of colorectal cancers, but little in known about how the mutant protein contributes to onset and progression of the disease. Using genetically engineered mice, we find that mutant N-Ras strongly promotes tumorigenesis in the context of inflammation. The pro-tumorigenic nature of mutant N-Ras is related to its anti-apoptotic function, which is mediated by [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel, pendant la phase de progression tumorale, la perte du gène p53 dans des entérocytes induit la formation d'un micro-environnement inflammatoire et une transition épithélio-mésenchymateuse dans des tumeurs du côlon-rectum

Loss of p53 in Enterocytes Generates an Inflammatory Microenvironment Enabling Invasion and Lymph Node Metastasis of Carcinogen-Induced Colorectal Tumors

Schwitalla, Sarah ; Ziegler, Paul K ; Horst, David ; Becker, Valentin ; Kerle, Irina ; Begus-Nahrmann, Yvonne ; Lechel, André ; Rudolph, K.  Lenhard ; Langer, Rupert ; Slotta-Huspenina, Julia ; Bader, Franz G ; Prazeres da Costa, Olivia ; Neurath, Markus F ; Meining, Alexander ; Kirchner, Thomas ; Greten, Florian R

Loss of p53 is considered to allow progression of colorectal tumors from the adenoma to the carcinoma stage. Using mice with an intestinal epithelial cell (IEC)-specific p53 deletion, we demonstrate that loss of p53 alone is insufficient to initiate intestinal tumorigenesis but markedly enhances carcinogen-induced tumor incidence and leads to invasive cancer and lymph node metastasis. Whereas p53 controls DNA damage and IEC survival during the initiation stage, loss of p53 during tumor [...]

Menée in vivo, cette étude met en évidence un mécanisme par lequel, dans des cellules épithéliales de tumeurs induites par ErbB2, la perte du gène Par3 favorise le processus métastatique d'un cancer du sein en diminuant la cohésion inter-cellulaire

Loss of Par3 promotes breast cancer metastasis by compromising cell–cell cohesion

Xue, Bin ; Krishnamurthy, Kannan ; Allred, D. Craig ; Muthuswamy, Senthil K.

The mechanisms by which tumour cells metastasize and the role that cell polarity proteins play in this process are not well understood. We report that partitioning defective protein 3 (Par3) is dysregulated in metastasis in human breast cancer, and is associated with a higher tumour grade and ErbB2-positive status. Downregulation of Par3 cooperated with ErbB2 to induce cell invasion and metastasis in vivo. Interestingly, the metastatic behaviour was not associated with an overt mesenchymal [...]

Menée à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lequels des exosomes secrétés par des fibroblastes du micro-environnement tumoral favorisent, via la signalisation Wnt-PCP, le processus invasif d'un cancer du sein

Exosomes Mediate Stromal Mobilization of Autocrine Wnt-PCP Signaling in Breast Cancer Cell Migration

Luga, Valbona ; Zhang, Liang ; Viloria-Petit, Alicia M ; Ogunjimi, Abiodun A ; Inanlou, Mohammad R ; Chiu, Elaine ; Buchanan, Marguerite ; Hosein, Abdel Nasser ; Basik, Mark ; Wrana, Jeffrey L

Stroma in the tumor microenvironment plays a critical role in cancer progression, but how it promotes metastasis is poorly understood. Exosomes are small vesicles secreted by many cell types and enable a potent mode of intercellular communication. Here, we report that fibroblast-secreted exosomes promote breast cancer cell (BCC) protrusive activity and motility via Wnt-planar cell polarity (PCP) signaling. We show that exosome-stimulated BCC protrusions display mutually exclusive localization [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par le micro-ARN 124 dans la régulation des processus invasif et métastatique d'un cancer du sein

MiR-124 Targets Slug to Regulate Epithelial-to-Mesenchymal Transition and Metastasis of Breast Cancer

Liang, Yong-Jun ; Wang, Qiu-Yu ; Zhou, Ci-Xiang ; Yin, Qian-Qian ; He, Ming ; Yu, Xiao-Ting ; Cao, Dan-Xia ; Chen, Guo-Qiang ; He, Jian-Rong ; Zhao, Qian

MicroRNAs have been integrated into tumorigenic programs as either oncogenes or tumor suppressor genes. The miR-124 was reported to be attenuated in several tumors, such as glioma, medulloblastoma and hepatocellular carcinoma. However, its roles on cancer remain greatly elusive. Here, we show that the miR-124 expression is significantly suppressed in human breast cancer specimens, which is reversely correlated to histological grade of the cancer. More intriguingly, ectopic expression of miR-124 [...]

Menée sur une lignée cellulaire, cette étude évalue la faisabilité d'une technique d'amplification appelée MALBAC pour détecter des variations de nombres de copies de gènes et de simples nucléotides à l'échelle d'une seule cellule

Genome-Wide Detection of Single-Nucleotide and Copy-Number Variations of a Single Human Cell

Zong, Chenghang ; Lu, Sijia ; Chapman, Alec R. ; Xie, X. Sunney

Kindred cells can have different genomes because of dynamic changes in DNA. Single-cell sequencing is needed to characterize these genomic differences but has been hindered by whole-genome amplification bias, resulting in low genome coverage. Here, we report on a new amplification method—multiple annealing and looping-based amplification cycles (MALBAC)—that offers high uniformity across the genome. Sequencing MALBAC-amplified DNA achieves 93% genome coverage ≥1x for a single human cell at 25x [...]

Cette étude évalue l'intérêt d'un modèle murin présentant une haplo-insuffisance du gène SMG1 pour l'étude du développement d'un cancer dans un contexte inflammatoire

Smg1 haploinsufficiency predisposes to tumor formation and inflammation

Roberts, Tara L. ; Ho, Uda ; Luff, John ; Lee, C. Soon ; Apte, Simon H. ; MacDonald, Kelli P. A. ; Raggat, Liza J. ; Pettit, Allison R. ; Morrow, Carl A. ; Waters, Michael J. ; Chen, Phil ; Woods, Rick G. ; Thomas, Gethin P. ; St. Pierre, Liam ; Farah, Camile S. ; Clarke, Raymond A. ; Brown, James A. L. ; Lavin, Martin F.

SMG1 is a member of the phosphoinositide kinase-like kinase family of proteins that includes ATM, ATR, and DNA-PK, proteins with known roles in DNA damage and cellular stress responses. SMG1 has a well-characterized role in nonsense-mediated decay as well as suggested roles in the DNA damage response, resistance to oxidative stress, regulation of hypoxic responses, and apoptosis. To understand the roles of SMG1 further, we generated a Genetrap Smg1 mouse model. Smg1 homozygous KO mice were [...]

Cet article passe en revue les travaux récents sur les modèles précliniques développés pour l'étude des cancers de la vessie

Current pre-clinical models for the advancement of translational bladder cancer research

DeGraff, David J. ; Robinson, Victoria L ; Shah, Jay B ; Brandt, William ; Sonpavde, Guru ; Kang, Yibin ; Liebert, Monica ; Wu, Xue-Ru ; Taylor, John A

Bladder cancer is a common disease representing the 5th most diagnosed solid tumor in the United States. In spite of this, advances in our understanding of the molecular etiology and treatment of bladder cancer have been relatively lacking. This is especially apparent when recent advances in other cancers, such as breast and prostate, are taken into consideration. The field of bladder cancer research is ready and poised for a series of paradigm-shifting discoveries that will greatly impact the [...]