Menée dans le cadre du projet "International Cancer Genome Consortium" sur 98 échantillons tumoraux prélevés sur des patients pédiatriques atteints d'un astrocytome pilocytique, cette étude identifie des anomalies récurrentes des gènes FGFR1, PTPN11 et NTRK2

Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma

Jones, David T. W. ; Hutter, Barbara ; Jager, Natalie ; Korshunov, Andrey ; Kool, Marcel ; Warnatz, Hans-Jörg ; Zichner, Thomas ; Lambert, Sally R. ; Ryzhova, Marina ; Quang, Dong Anh Khuong ; Fontebasso, Adam M. ; Stutz, Adrian M. ; Hutter, Sonja ; Zuckermann, Marc ; Sturm, Dominik ; Gronych, Jan ; Lasitschka, Barbel ; Schmidt, Sabine ; Seker-Cin, Huriye ; Witt, Hendrik ; Sultan, Marc ; Ralser, Meryem ; Northcott, Paul A. ; Hovestadt, Volker ; Bender, Sebastian ; Pfaff, Elke ; Stark, Sebastian ; Faury, Damien ; Schwartzentruber, Jeremy ; Majewski, Jacek ; Weber, Ursula D. ; Zapatka, Marc ; Raeder, Benjamin ; Schlesner, Matthias ; Worth, Catherine L. ; Bartholomae, Cynthia C. ; von Kalle, Christof ; Imbusch, Charles D. ; Radomski, Sylwester ; Lawerenz, Chris ; van Sluis, Peter ; Koster, Jan ; Volckmann, Richard ; Versteeg, Rogier ; Lehrach, Hans ; Monoranu, Camelia ; Winkler, Beate ; Unterberg, Andreas ; Herold-Mende, Christel ; Milde, Till ; Kulozik, Andreas E. ; Ebinger, Martin ; Schuhmann, Martin U. ; Cho, Yoon-Jae ; Pomeroy, Scott L. ; von Deimling, Andreas ; Witt, Olaf ; Taylor, Michael D. ; Wolf, Stephan ; Karajannis, Matthias A. ; Eberhart, Charles G. ; Scheurlen, Wolfram ; Hasselblatt, Martin ; Ligon, Keith L. ; Kieran, Mark W. ; Korbel, Jan O. ; Yaspo, Marie-Laure ; Brors, Benedikt ; Felsberg, Jörg ; Reifenberger, Guido ; Collins, V. Peter ; Jabado, Nada ; Eils, Roland ; Lichter, Peter ; the International Cancer Genome Consortium PedBrain Tumor, Project

Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, en régulant le métabolisme des cellules tumorales, TAp73, structurellement homologue au suppresseur de tumeurs p53, favorise la prolifération cellulaire

TAp73 enhances the pentose phosphate pathway and supports cell proliferation

Du, Wenjing ; Jiang, Peng ; Mancuso, Anthony ; Stonestrom, Aaron ; Brewer, Michael D. ; Minn, Andy J. ; Mak, Tak W. ; Wu, Mian ; Yang, Xiaolu

TAp73 is a structural homologue of the pre-eminent tumour suppressor p53. However, unlike p53, TAp73 is rarely mutated, and instead is frequently overexpressed in human tumours. It remains unclear whether TAp73 affords an advantage to tumour cells and if so, what the underlying mechanism is. Here we show that TAp73 supports the proliferation of human and mouse tumour cells. TAp73 activates the expression of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels la protéine de fusion AML1-ETO, issue de la translocation t(8;21), favorise le développement d'une leucémie myéloïde aiguë

A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis

Sun, Xiao-Jian ; Wang, Zhanxin ; Wang, Lan ; Jiang, Yanwen ; Kost, Nils ; Soong, T. David ; Chen, Wei-Yi ; Tang, Zhanyun ; Nakadai, Tomoyoshi ; Elemento, Olivier ; Fischle, Wolfgang ; Melnick, Ari ; Patel, Dinshaw J. ; Nimer, Stephen D. ; Roeder, Robert G.

Transcription factors are frequently altered in leukaemia through chromosomal translocation, mutation or aberrant expression. AML1–ETO, a fusion protein generated by the t(8;21) translocation in acute myeloid leukaemia, is a transcription factor implicated in both gene repression and activation. AML1–ETO oligomerization, mediated by the NHR2 domain, is critical for leukaemogenesis, making it important to identify co-regulatory factors that ‘read’ the NHR2 oligomerization and contribute to [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par le gène TET1 dans le développement d'une leucémie avec réarrangements MLL

TET1 plays an essential oncogenic role in MLL-rearranged leukemia

Huang, Hao ; Jiang, Xi ; Li, Zejuan ; Li, Yuanyuan ; Song, Chun-Xiao ; He, Chunjiang ; Sun, Miao ; Chen, Ping ; Gurbuxani, Sandeep ; Wang, Jiapeng ; Hong, Gia-Ming ; Elkahloun, Abdel G. ; Arnovitz, Stephen ; Wang, Jinhua ; Szulwach, Keith ; Lin, Li ; Street, Craig ; Wunderlich, Mark ; Dawlaty, Meelad ; Neilly, Mary Beth ; Jaenisch, Rudolf ; Yang, Feng-Chun ; Mulloy, James C. ; Jin, Peng ; Liu, Paul P. ; Rowley, Janet D. ; Xu, Mingjiang ; He, Chuan ; Chen, Jianjun

The ten-eleven translocation 1 (TET1) gene is the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine to 5-hydroxymethylcytosine. Although TET1 was first identified as a fusion partner of the mixed lineage leukemia (MLL) gene in acute myeloid leukemia carrying t(10,11), its definitive role in leukemia is unclear. In contrast to the frequent down-regulation (or loss-of-function mutations) and critical tumor-suppressor roles of the three TET genes observed in [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels, en induisant une réponse de l'épithélium prostatique à une signalisation aberrante provoquée par la perte d'expression de PTEN, les facteurs de transcription ETS favorisent la tumorigenèse

ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss

Chen, Yu ; Chi, Ping ; Rockowitz, Shira ; Iaquinta, Phillip J. ; Shamu, Tambudzai ; Shukla, Shipra ; Gao, Dong ; Sirota, Inna ; Carver, Brett S. ; Wongvipat, John ; Scher, Howard I. ; Zheng, Deyou ; Sawyers, Charles L.

Studies of ETS-mediated prostate oncogenesis have been hampered by a lack of suitable experimental systems. Here we describe a new conditional mouse model that shows robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, the mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG markedly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel, via le récepteur endothélial P2Y2, les thrombocytes favorisent le processus métastatique

Platelet-Derived Nucleotides Promote Tumor-Cell Transendothelial Migration and Metastasis via P2Y2 Receptor

Schumacher, Dagmar ; Strilic, Boris ; Sivaraj, Kishor Kumar ; Wettschureck, Nina ; Offermanns, Stefan

Tumor cells can activate platelets, which in turn facilitate tumor cell survival and dissemination. The exact mechanisms by which platelets promote metastasis have remained unclear. Here, we show that adenine nucleotides released from tumor cell-activated platelets induce opening of the endothelial barrier to allow transendothelial migration of tumor cells and thereby promote cancer cell extravasation. We identified the endothelial P2Y2 receptor, which is activated by ATP, as the primary [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en régulant l'e-cadhérine, l'acquisition de l'expression du facteur de transcription NFATc1 par les cellules cancéreuses favorise le processus invasif

Acquired expression of NFATc1 downregulates E-cadherin and promotes cancer cell invasion

Oikawa, Tsukasa ; Nakamura, Atsuko ; Onishi, Nobuyuki ; Yamada, Taketo ; Matsuo, Koichi ; Saya, Hideyuki

NFATc1 is a transcription factor that regulates T cell development, osteoclastogenesis, and macrophage function. Given that T cells, osteoclasts, and macrophages in the tumor microenvironment are thought to modulate tumor progression, tumor cells may acquire NFATc1 expression through fusion with these NFATc1-expressing normal cells. We here revealed that a small proportion of tumor cells in human carcinoma specimens expressed NFATc1. To investigate the consequences of NFATc1 acquisition by [...]

Menée in vitro, à l'aide de xénogreffes et à partir d'échantillons tumoraux prélevés sur des patients atteints d'un carcinome épidermoïde de l'œsophage, cette étude met en évidence des mécanismes par lesquels, en régulant la signalisation de la calréticuline (une protéine chaperon), l'enzyme PTP1B favorise le processus métastatique

Protein-Tyrosine Phosphatase 1B Contributes to Calreticulin-Induced Cell Migration and Metastasis of Esophageal Squamous Cell Carcinoma

Wang, Xiao-Min ; Shang, Li ; Zhang, Yu ; Hao, Jia-Jie ; Shi, Feng ; Luo, Wei ; Zhang, Tong-Tong ; Wang, Bo-Shi ; Yang, Yang ; Liu, Zhi-Hua ; Zhan, Qi-Min ; Wang, Ming-Rong

Calreticulin (CRT) is a Ca2+-binding protein that alters Ca2+-homeostasis in the endoplasmic reticulum (ER) by acting as a chaperone in cells. We previously showed that CRT was overexpressed in esophageal squamous cell carcinoma (ESCC), and elevated CRT expression promoted the migration and invasion of ESCC cells. In the present study, we investigate the mechanisms underlying role of CRT in esophageal carcinoma progression. We found that depletion of CRT or protein-tyrosine phosphatase 1B [...]

Après avoir passé en revue les travaux récents sur les mécanismes associés à la progression d'un cancer de la prostate, cet article présente un nouveau modèle permettant de mieux rendre compte du phénomène et de mettre en place de meilleures stratégies thérapeutiques sur la base d'une classification moléculaire adaptée

Molecular Classification of Prostate Cancer Progression: Foundation for Marker-Driven Treatment of Prostate Cancer

Logothetis, Christopher J. ; Gallick, Gary E. ; Maity, Sankar N. ; Kim, Jeri ; Aparicio, Ana ; Efstathiou, Eleni ; Lin, Sue-Hwa

Recently, many therapeutic agents for prostate cancer have been approved that target the androgen receptor and/or the prostate tumor microenvironment. Each of these therapies has modestly increased patient survival. A better understanding of when in the course of prostate cancer progression specific therapies should be applied, and of what biomarkers would indicate when resistance arises, would almost certainly improve survival due to these therapies. Thus, applying the armamentarium of [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels une surexpression du récepteur GPR48 favorise les processus invasif et métastatique d'un cancer colorectal

GPR48, a poor prognostic factor, promotes tumor metastasis and activates β-catenin/TCF signaling in colorectal cancer

Wu, Jinhua ; Xie, Na ; Xie, Ke ; Zeng, Jun ; Cheng, Lin ; Lei, Yunlong ; Liu, Yuan ; Song, Linhong ; Dong, Dandan ; Chen, Yi ; Zeng, Rui ; Nice, Edouard C. ; Huang, Canhua ; Wei, Yuquan

G protein-coupled receptor 48 (GPR48) is an orphan receptor belonging to the G protein-coupled receptors (GPCRs) family, which plays an important role in the development of various organs and cancer development and progression such as gastric cancer and colorectal cancer. However, the prognostic value of GPR48 expression in patients with CRC has not been reported. In this study, we observed that GPR48 was overexpressed in primary CRC and metastatic lymph nodes, and closely correlated with tumor [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant la signalisation TGF-β, l'enzyme PAD4 favorise la transition épithélio-mésenchymateuse dans une tumeur mammaire

Dysregulation of PAD4-mediated citrullination of nuclear GSK3β activates TGF-β signaling and induces epithelial-to-mesenchymal transition in breast cancer cells

Stadler, Sonja C. ; Vincent, C. Theresa ; Fedorov, Victor D. ; Patsialou, Antonia ; Cherrington, Brian D. ; Wakshlag, Joseph J. ; Mohanan, Sunish ; Zee, Barry M. ; Zhang, Xuesen ; Garcia, Benjamin A. ; Condeelis, John S. ; Brown, Anthony M. C. ; Coonrod, Scott A. ; Allis, C. David

Peptidylarginine deiminase 4 (PAD4) is a Ca2+-dependent enzyme that converts arginine and methylarginine residues to citrulline, with histone proteins being among its best-described substrates to date. However, the biological function of this posttranslational modification, either in histones or in nonhistone proteins, is poorly understood. Here, we show that PAD4 recognizes, binds, and citrullinates glycogen synthase kinase-3β (GSK3β), both in vitro and in vivo. Among other functions, GSK3β is [...]

Menée in vivo, cette étude met en évidence le rôle joué par la forme alternativement épissée du facteur tissulaire dans la progression d'un cancer du sein

Alternatively spliced tissue factor promotes breast cancer growth in a β1 integrin-dependent manner

Kocatürk, Begüm ; Van den Berg, Yascha W. ; Tieken, Chris ; Mieog, J. Sven D. ; de Kruijf, Esther M. ; Engels, Charla C. ; van der Ent, Martijn A. ; Kuppen, Peter J. ; Van de Velde, Cornelis J. ; Ruf, Wolfram ; Reitsma, Pieter H. ; Osanto, Susanne ; Liefers, Gerrit-Jan ; Bogdanov, Vladimir Y. ; Versteeg, Henri H.

Full-length tissue factor (flTF), the coagulation initiator, is overexpressed in breast cancer (BrCa), but associations between flTF expression and clinical outcome remain controversial. It is currently not known whether the soluble alternatively spliced TF form (asTF) is expressed in BrCa or impacts BrCa progression. We are unique in reporting that asTF, but not flTF, strongly associates with both tumor size and grade, and induces BrCa cell proliferation by binding to β1 integrins. asTF [...]

Menée sur des lignées cellulaires, à l'aide de xénogreffes et à partir d'échantillons tumoraux prélevés sur des patients atteints d'un glioblastome, cette étude met en évidence le rôle joué par la voie de signalisation ZEB1 dans le processus invasif

The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance

Siebzehnrubl, Florian A. ; Silver, Daniel J. ; Tugertimur, Bugra ; Deleyrolle, Loic P. ; Siebzehnrubl, Dorit ; Sarkisian, Matthew R. ; Devers, Kelly G. ; Yachnis, Antony T. ; Kupper, Marius D. ; Neal, Daniel ; Nabilsi, Nancy H. ; Kladde, Michael P. ; Suslov, Oleg ; Brabletz, Simone ; Brabletz, Thomas ; Reynolds, Brent A. ; Steindler, Dennis A.

Glioblastoma remains one of the most lethal types of cancer, and is the most common brain tumour in adults. In particular, tumour recurrence after surgical resection and radiation invariably occurs regardless of aggressive chemotherapy. Here, we provide evidence that the transcription factor ZEB1 (zinc finger E-box binding homeobox 1) exerts simultaneous influence over invasion, chemoresistance and tumourigenesis in glioblastoma. ZEB1 is preferentially expressed in invasive glioblastoma cells, [...]

Cet article passe en revue les travaux récents mettant en oeuvre des modèles en réseau pour interpréter les résultats d'études à base d'ARN-interférents dans le cancer

Integrated Network Analyses for Functional Genomic Studies in Cancer

Wilson, Jennifer L. ; Hemann, Michael T. ; Fraenkel, Ernest ; Lauffenburger, Douglas A.

RNA-interference (RNAi) studies hold great promise for functional investigation of the significance of genetic variations and mutations, as well as potential synthetic lethalities, for understanding and treatment of cancer, yet technical and conceptual issues currently diminish the potential power of this approach. While numerous research groups are usefully employing this kind of functional genomic methodology to identify molecular mediators of disease severity, response, and resistance to [...]

Cet article passe en revue les travaux récents sur les bases moléculaires du phénotype méthylateur des ilôts CpG dans divers types de cancers

The CpG island methylator phenotype: what's in a name?

Hughes, Laura A.E. ; Melotte, Veerle ; de Schrijver, Joachim ; de Maat, Michiel ; Smit, Vincent T.H.B.M. ; Bovee, Judith V.M.G. ; French, Pim J. ; van den Brandt, Piet A. ; Schouten, Leo J ; de Meyer, Tim ; Van Criekinge, Wim ; Ahuja, Nita ; Herman, James G. ; Weijenberg, Matty P. ; van Engeland, Manon

Although the CpG island methylator phenotype (CIMP) was first identified and has been most extensively studied in colorectal cancer, the term 'CIMP' has been repeatedly used over the past decade to describe CpG island promoter methylation in other tumor types, including bladder, breast, endometrial, gastric, glioblastoma (gliomas), hepatocellular, lung, ovarian, pancreatic, renal cell and prostate cancers, as well as for leukemia, melanoma, duodenal adenocarninomas, adrenocortical carcinomas, [...]

Menée sur 747 échantillons tumoraux fixés au formol et inclus en paraffine après prélèvement sur des patients atteints d'un cancer colorectal, cette étude évalue les performances d'une méthode à base de microscopie en fluorescence pour mener une analyse à l'échelle de cellules uniques et révéler l'hétérogénéité tumorale

Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue

Gerdes, Michael J. ; Sevinsky, Christopher J. ; Sood, Anup ; Adak, Sudeshna ; Bello, Musodiq O. ; Bordwell, Alexander ; Can, Ali ; Corwin, Alex ; Dinn, Sean ; Filkins, Robert J. ; Hollman, Denise ; Kamath, Vidya ; Kaanumalle, Sireesha ; Kenny, Kevin ; Larsen, Melinda ; Lazare, Michael ; Li, Qing ; Lowes, Christina ; McCulloch, Colin C. ; McDonough, Elizabeth ; Montalto, Michael C. ; Pang, Zhengyu ; Rittscher, Jens ; Santamaria-Pang, Alberto ; Sarachan, Brion D. ; Seel, Maximilian L. ; Seppo, Antti ; Shaikh, Kashan ; Sui, Yunxia ; Zhang, Jingyu ; Ginty, Fiona

Limitations on the number of unique protein and DNA molecules that can be characterized microscopically in a single tissue specimen impede advances in understanding the biological basis of health and disease. Here we present a multiplexed fluorescence microscopy method (MxIF) for quantitative, single-cell, and subcellular characterization of multiple analytes in formalin-fixed paraffin-embedded tissue. Chemical inactivation of fluorescent dyes after each image acquisition round allows reuse of [...]