Menée sur des échantillons tumoraux prélevés sur des patients atteints d'un rhadomyosarcome à cellules du fuseau (14 enfants, 7 adultes), cette étude met en évidence des réarrangements du gène NCOA2 chez les jeunes enfants et les patients atteints de la forme congénitale de la maladie

Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma

Mosquera, Juan Miguel ; Sboner, Andrea ; Zhang, Lei ; Kitabayashi, Naoki ; Chen, Chun-Liang ; Sung, Yun Shao ; Wexler, Leonard H. ; LaQuaglia, Michael P. ; Edelman, Morris ; Sreekantaiah, Chandrika ; Rubin, Mark A. ; Antonescu, Cristina R.

Spindle cell rhabdomyosarcoma (RMS) is a rare form of RMS with different clinical characteristics between children and adult patients. Its genetic hallmark remains unknown and it remains debatable if there is pathogenetic relationship between the spindle cell and the so-called sclerosing RMS. We studied two pediatric and one adult spindle cell RMS by next generation RNA sequencing and FusionSeq data analysis to detect novel fusions. An SRF-NCOA2 fusion was detected in a spindle cell RMS from [...]

Cette étude chinoise passe en revue les mécanismes impliquant des édipokines dans le développement d'un carcinome hépatocellulaire

Obesity, adipokines and hepatocellular carcinoma

Duan, Xiao-Feng ; Tang, Peng ; Li, Qiang ; Yu, Zhen-Tao

Obesity is rapidly becoming pandemic and is associated with increased carcinogenesis, especially hepatocellular carcinoma (HCC). Adipose tissue is considered as an endocrine organ because of its capacity to secrete a variety of adipokines, such as leptin, adiponectin and resistin. Recently, adipokines have been demonstrated to be associated with kinds of chronic liver diseases including fibrosis, cirrhosis and carcinogenesis. Direct evidence is accumulating rapidly supporting the inhibitory [...]

Menée in vitro à l'aide d'une technique de résonance magnétique nucléaire, cette étude évalue la faisabilité de mesurer en temps réel l'hyperactivation du réseau de signalisation RAS induite par des mutations oncogéniques

NMR-based functional profiling of RASopathies and oncogenic RAS mutations

Smith, Matthew J. ; Neel, Benjamin G. ; Ikura, Mitsuhiko

Defects in the RAS small G protein or its associated network of regulatory proteins that disrupt GTPase cycling are a major cause of cancer and developmental RASopathy disorders. Lack of robust functional assays has been a major hurdle in RAS pathway-targeted drug development. We used NMR to obtain detailed mechanistic data on RAS cycling defects conferred by oncogenic mutations, or full-length RASopathy-derived regulatory proteins. By monitoring the conformation of wild-type and oncogenic RAS [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme de régulation du cycle cellulaire et de l'instabilité génomique par le gène suppresseur de tumeurs SirT2

The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation

Serrano, Lourdes ; Martínez-Redondo, Paloma ; Marazuela-Duque, Anna ; Vazquez, Berta N. ; Dooley, Scott J. ; Voigt, Philipp ; Beck, David B. ; Kane-Goldsmith, Noriko ; Tong, Qiang ; Rabanal, Rosa M. ; Fondevila, Dolors ; Muñoz, Purificación ; Krüger, Marcus ; Tischfield, Jay A. ; Vaquero, Alejandro

The establishment of the epigenetic mark H4K20me1 (monomethylation of H4K20) by PR-Set7 during G2/M directly impacts S-phase progression and genome stability. However, the mechanisms involved in the regulation of this event are not well understood. Here we show that SirT2 regulates H4K20me1 deposition through the deacetylation of H4K16Ac (acetylation of H4K16) and determines the levels of H4K20me2/3 throughout the cell cycle. SirT2 binds and deacetylates PR-Set7 at K90, modulating its chromatin [...]

Cet article passe en revue les travaux récents sur le rôle de la voie de signalisation Hippo dans les cancers

The Hippo pathway and human cancer

Harvey, Kieran F. ; Zhang, Xiaomeng ; Thomas, David M.

The Hippo pathway controls organ size in diverse species, whereas pathway deregulation can induce tumours in model organisms and occurs in a broad range of human carcinomas, including lung, colorectal, ovarian and liver cancer. Despite this, somatic or germline mutations in Hippo pathway genes are uncommon, with only the upstream pathway gene neurofibromin 2 (NF2) recognized as a bona fide tumour suppressor gene. In this Review, we appraise the evidence for the Hippo pathway as a cancer [...]

Menée sur des lignées cellulaires, cette étude met en évidence le rôle joué par la voie de signalisation TYK2-STAT1-BCL2 dans les leucémies aiguës lymphoblastiques T

TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia

Sanda, Takaomi ; Tyner, Jeffrey W. ; Gutierrez, Alejandro ; Ngo, Vu N ; Glover, Jason ; Chang, Bill H ; Yost, Arla ; Ma, Wenxue ; Fleischman, Angela G ; Zhou, Wenjun ; Yang, Yandan ; Kleppe, Maria ; Ahn, Yebin ; Tatarek, Jessica ; Kelliher, Michelle ; Neuberg, Donna ; Levine, Ross L ; Moriggl, Richard ; Muller, Mathias ; Gray, Nathanael S. ; Jamieson, Catriona HM ; Weng, Andrew P ; Staudt, Louis M ; Druker, Brian J ; Look, A. Thomas

Targeted molecular therapy has yielded remarkable outcomes in certain cancers, but specific therapeutic targets remain elusive for many others. As a result of two independent RNA interference (RNAi) screens, we identified pathway dependence on a member of the JAK tyrosine kinase family, TYK2, and its downstream effector STAT1 in T-cell acute lymphoblastic leukemia (T-ALL). Gene knockdown experiments consistently demonstrated TYK2 dependence in both T-ALL primary specimens and cell lines, and a [...]

Cet article passe en revue les travaux récents sur les mécanismes biologiques communs à la bronchopneumopathie chronique obstructive et au cancer du poumon

Mechanistic links between COPD and lung cancer

Houghton, A. McGarry

Numerous epidemiological studies have consistently linked the presence of chronic obstructive pulmonary disease (COPD) to the development of lung cancer, independently of cigarette smoking dosage. The mechanistic explanation for this remains poorly understood. Progress towards uncovering this link has been hampered by the heterogeneous nature of the two disorders: each is characterized by multiple sub-phenotypes of disease. In this Review, I discuss the nature of the link between the two [...]

Menée sur des échantillons prélevés dans des tumeurs, des ganglions lymphatiques et du sang périphérique de patients atteints d'un carcinome épidermoïde de la tête et du cou, cette étude met en évidence des mécanismes par lequels la protéine STAT3 régule l'expression de l'arginase-1 dans les cellules myéloïdes suppressives

STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients

Vasquez-Dunddel, David ; Pan, Fan ; Zeng, Qi ; Gorbounov, Mikhail ; Albesiano, Emilia ; Fu, Juan ; Blosser, Richard L. ; Tam, Ada J. ; Bruno, Tullia ; Zhang, Hao ; Pardoll, Drew ; Kim, Young

Myeloid-derived suppressor cells (MDSC) play a key immunosuppressive role in various types of cancer, including head and neck squamous cell carcinoma (HNSCC). In this study, we characterized CD14+HLA-DR–/lo cells sorted from the tumors, draining lymph nodes, and peripheral blood of HNSCC patients. CD14+HLA-DR–/lo cells were phenotyped as CD11b+, CD33+, CD34+, arginase-I+, and ROS+. In all 3 compartments, they suppressed autologous, antigen-independent T cell proliferation in a differential [...]

Menée sur des lignées cellulaires et des échantillons prélevés sur 2 430 patients atteints d'un cancer, cette étude met en évidence une assocation entre l'expression des gènes Myc et Ran dans les cancers du poumon et du sein

RanGTPase: A Candidate for Myc-Mediated Cancer Progression

Yuen, Hiu-Fung ; Gunasekharan, Vignesh-Kumar ; Chan, Ka-Kui ; Zhang, Shu-Dong ; Platt-Higgins, Angela ; Gately, Kathy ; O’Byrne, Ken ; Fennell, Dean A. ; Johnston, Patrick G. ; Rudland, Philip S. ; El-Tanani, Mohamed

Background Ras-related nuclear protein (Ran) is required for cancer cell survival in vitro and human cancer progression, but the molecular mechanisms are largely unknown. Methods We investigated the effect of the v-myc myelocytomatosis viral oncogene homolog (Myc) on Ran expression by Western blot, chromatin immunoprecipitation, and luciferase reporter assays and the effects of Myc and Ran expression in cancer cells by soft-agar, cell adhesion, and invasion assays. The correlation between Myc [...]

Menée à l'aide de modèles de compensation colonisation/compétition, cette étude suggère un mécanisme de nature évolutionniste permettant de rendre compte de l'hétérogénéité génétique intratumorale observée dans de nombreuses formes de cancer

Tumor evolution in space: the effects of competition colonization tradeoffs on tumor invasion dynamics

Orlando,Paul A ; Gatenby,Robert A ; Brown,Joel S

We apply competition colonization tradeoff models to tumor growth and invasion dynamics to explore the hypothesis that varying selection forces will result in predictable phenotypic differences in cells at the tumor invasive front compared to those in the core. Spatially, ecologically, and evolutionarily explicit partial differential equation models of tumor growth confirm that spatial invasion produces selection pressure for motile phenotypes. The effects of the invasive phenotype on normal [...]

Cet article passe en revue les travaux récents sur le rôle des micro-ARNs dans la régulation des cellules souches cancéreuses et de la transition épithélio-mésenchymateuse

MicroRNAs regulate both epithelial-to-mesenchymal transition and cancer stem cells

Ceppi, P. ; Peter, M. E.

Concepts and experimental models derived from basic research have been successfully applied to the field of molecular oncology, tremendously increasing our knowledge of the nature and the progression of tumors. The process of epithelial-to-mesenchymal transition, the cancer stem cell hypothesis, and their functional association and interdependence represent some of the most significant examples. The molecular determinants underlying the plasticity of cancers are currently the object of [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en régulant la voie de signalisation TGF-β, l'ubiquitine ligase Arkadia joue un rôle crucial dans les phases précoces du processus métastatique

Arkadia Regulates Tumor Metastasis by Modulation of the TGF-β Pathway

Briones-Orta, Marco A. ; Levy, Laurence ; Madsen, Chris D. ; Das, Debipriya ; Erker, Yigit ; Sahai, Erik ; Hill, Caroline S.

TGF-β can act as a tumor suppressor at early stages of cancer progression and as a tumor promoter at later stages. The E3 ubiquitin ligase Arkadia (RNF111) is a critical component of the TGF-β signaling pathway, being required for a subset of responses, those mediated by Smad3–Smad4 complexes. It acts by mediating ligand-induced degradation of Ski and SnoN (SKIL), which are 2 potent transcriptional repressors. Here, we investigate the role of Arkadia in cancer using model systems to address [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par les anticorps de la sous-classe IgG4 dans l'échappement d'une tumeur de mélanome au système immunitaire

IgG4 subclass antibodies impair antitumor immunity in melanoma

Karagiannis, Panagiotis ; Gilbert, Amy E. ; Josephs, Debra H. ; Ali, Niwa ; Dodev, Tihomir ; Saul, Louise ; Correa, Isabel ; Roberts, Luke ; Beddowes, Emma ; Koers, Alexander ; Hobbs, Carl ; Ferreira, Silvia ; Geh, Jenny L. C. ; Healy, Ciaran ; Harries, Mark ; Acland, Katharine M. ; Blower, Philip J. ; Mitchell, Tracey ; Fear, David J. ; Spicer, James F. ; Lacy, Katie E. ; Nestle, Frank O. ; Karagiannis, Sophia N.

Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10–driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22+ B cells and IgG4+-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la petite GTPase ARF6 régule les processus invasif et métastatique d'un mélanome

The Small GTPase ARF6 Stimulates {beta}-Catenin Transcriptional Activity During WNT5A-Mediated Melanoma Invasion and Metastasis

Grossmann, Allie H. ; Yoo, Jae Hyuk ; Clancy, James ; Sorensen, Lise K. ; Sedgwick, Alanna ; Tong, Zongzhong ; Ostanin, Kirill ; Rogers, Aaron ; Grossmann, Kenneth F. ; Tripp, Sheryl R. ; Thomas, Kirk R. ; D'Souza-Schorey, Crislyn ; Odelberg, Shannon J. ; Li, Dean Y.

β-Catenin has a dual function in cells: fortifying cadherin-based adhesion at the plasma membrane and activating transcription in the nucleus. We found that in melanoma cells, WNT5A stimulated the disruption of N-cadherin and β-catenin complexes by activating the guanosine triphosphatase adenosine diphosphate ribosylation factor 6 (ARF6). Binding of WNT5A to the Frizzled 4

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel les cellules stromales mésenchymateuses de la moelle osseuse favorisent la progression d'un myélome multiple

BM mesenchymal stromal cell–derived exosomes facilitate multiple myeloma progression

Roccaro, Aldo M. ; Sacco, Antonio ; Maiso, Patricia ; Azab, Abdel Kareem ; Tai, Yu-Tzu ; Reagan, Michaela ; Azab, Feda ; Flores, Ludmila M. ; Campigotto, Federico ; Weller, Edie ; Anderson, Kenneth C. ; Scadden, David T. ; Ghobrial, Irene M.

BM mesenchymal stromal cells (BM-MSCs) support multiple myeloma (MM) cell growth, but little is known about the putative mechanisms by which the BM microenvironment plays an oncogenic role in this disease. Cell-cell communication is mediated by exosomes. In this study, we showed that MM BM-MSCs release exosomes that are transferred to MM cells, thereby resulting in modulation of tumor growth in vivo. Exosomal microRNA (miR) content differed between MM and normal BM-MSCs, with a lower content of [...]

Cet article passe en revue les travaux récents sur le rôle des micro-ARNs dans la régulation de la tumorigenèse et de la progression d'un cancer de la prostate

Roles of microRNAs during prostatic tumorigenesis and tumor progression

Fang, Y. X. ; Gao, W. Q.

Prostate cancer (PCa) is considered to be a frequently diagnosed cancer in males with high mortality worldwide, but the molecular mechanism responsible for prostate tumorigenesis and progression remains unclear. Increasing evidence has shown that microRNAs (miRNAs) play an important role in PCa. In this review, we focus on the current advances about the role of miRNAs in regulating tumorigenesis and progression of PCa, mainly in suppressing or promoting PCa growth and metastasis, and [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en activant la signalisation Notch, des astrocytes favorisent la formation de métastases cérébrales d'un cancer du sein

Reactive astrocytes promote the metastatic growth of breast cancer stem-like cells by activating Notch signalling in brain

Xing, Fei ; Kobayashi, Aya ; Okuda, Hiroshi ; Watabe, Misako ; Pai, Sudha K. ; Pandey, Puspa R. ; Hirota, Shigeru ; Wilber, Andrew ; Mo, Yin-Yuan ; Moore, Brian E. ; Liu, Wen ; Fukuda, Koji ; Iiizumi, Megumi ; Sharma, Sambad ; Liu, Yin ; Wu, Kerui ; Peralta, Elizabeth ; Watabe, Kounosuke

Brain metastasis of breast cancer profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the 1 year survival rate among these patients remains less than 20%. However, the pathological mechanism of brain metastasis is as yet poorly understood. In this report, we found that metastatic breast tumour cells in the brain highly expressed IL-1β which then ‘activated’ surrounding astrocytes. This activation significantly augmented the expression of JAG1 in the [...]

Menée in vitro, cette étude analyse les interactions entre micro-ARNs et ARN messagers impliqués dans le processus invasif d'un cancer du sein

A systematic evaluation of miRNA:mRNA interactions involved in the migration and invasion of breast cancer cells

Luo, Daya ; Wilson, James ; Harvel, Nikki ; Liu, Jimei ; Pei, Lirong ; Huang, Shuang ; Hawthorn, LesleyAnn ; Shi, Huidong

In this study we performed a systematic evaluation of functional miRNA-mRNA interactions associated with the invasiveness of breast cancer cells using a combination of integrated miRNA and mRNA expression profiling, bioinformatics prediction, and functional assays. Analysis of the miRNA expression identified 11 miRNAs that were differentially expressed, including 7 down-regulated (miR-200c, miR-205, miR-203, miR-141, miR-34a, miR-183, and miR-375) and 4 up-regulated miRNAs (miR-146a, miR-138, [...]