Accueil Nota Bene Cancer V2 Numéro 100 du 25 August 2011 Biologie

Nota Bene Cancer Numéro 100 du 25 August 2011

Biologie

Aberrations chromosomiques

Menée sur 32 tumeurs de carcinome épidermoïde de la tête et du cou, cette étude de séquençage des exons identifie des mutations inactivant le gène NOTCH1

Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1
• Science, sous presse, 2011 (résumé)

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Menée sur 32 tumeurs de carcinome épidermoïde de la tête et du cou, cette étude de séquençage des exons identifie des mutations inactivant le gène NOTCH1

“Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1”

• Agrawal, Nishant;Frederick, Mitchell J.;Pickering, Curtis R.;Bettegowda, Chetan;Chang, Kyle;Li, Ryan J.;Fakhry, Carole;Xie, Tong-Xin;Zhang, Jiexin;Wang, Jing;Zhang, Nianxiang;El-Naggar, Adel K.;Jasser, Samar A.;Weinstein, John N.;Treviño, Lisa;Drummond, Jennifer A.;Muzny, Donna M.;Wu, Yuanqing;Wood, Laura D.;Hruban, Ralph H.;Westra, William H.;Koch, Wayne M.;Califano, Joseph A.;Gibbs, Richard A.;Sidransky, David;Vogelstein, Bert;Velculescu, Victor E.;Papadopoulos, Nickolas;Wheeler, David A.;Kinzler, Kenneth W.;Myers, Jeffrey N.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papilloma virus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA and HRAS, we identified mutations in FBXW7 and NOTCH1. Interestingly, nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.

Mots clés : Voies aérodigestives supérieures; Biologie (Aberrations chromosomiques)

Menée sur 7 tumeurs d'oligodendrogliomes, cette étude de séquençage des exons identifie des mutations des gènes CIC et FUBP1 associées au développement de la maladie

Mutations in CIC and FUBP1 Contribute to Human Oligodendroglioma
• Science, sous presse, 2011 (résumé)

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Menée sur 7 tumeurs d'oligodendrogliomes, cette étude de séquençage des exons identifie des mutations des gènes CIC et FUBP1 associées au développement de la maladie

“Mutations in CIC and FUBP1 Contribute to Human Oligodendroglioma”

• Bettegowda, Chetan;Agrawal, Nishant;Jiao, Yuchen;Sausen, Mark;Wood, Laura D.;Hruban, Ralph H.;Rodriguez, Fausto J.;Cahill, Daniel P.;McLendon, Roger;Riggins, Gregory;Velculescu, Victor E.;Oba-Shinjo, Sueli Mieko;Marie, Suely Kazue Nagahashi;Vogelstein, Bert;Bigner, Darell;Yan, Hai;Papadopoulos, Nickolas;Kinzler, Kenneth W.

Oligodendrogliomas are the second most common malignant brain tumor in adults and exhibit characteristic losses of chromosomes 1p and 19q. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven tumors. Among other changes, we found that the CIC gene (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six cases and that the FUBP1 gene [encoding far upstream element (FUSE) binding protein] on chromosome 1p was somatically mutated in two tumors. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes.

Mots clés : Système nerveux central; Biologie (Aberrations chromosomiques)

Menée initialement sur 13 cas de lymphome diffus à grandes cellules B et un cas de lymphome folliculaire, puis sur 113 cas de lymphome non hodgkinien, cette étude identifie des mutations fréquentes de gènes impliqués dans la modification des histones

Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma
• Nature, Vol. 476 (7360), pp. 298-303, 2011 (résumé)

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Menée initialement sur 13 cas de lymphome diffus à grandes cellules B et un cas de lymphome folliculaire, puis sur 113 cas de lymphome non hodgkinien, cette étude identifie des mutations fréquentes de gènes impliqués dans la modification des histones

“Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma”

• Morin, Ryan D.;Mendez-Lago, Maria;Mungall, Andrew J.;Goya, Rodrigo;Mungall, Karen L.;Corbett, Richard D.;Johnson, Nathalie A.;Severson, Tesa M.;Chiu, Readman;Field, Matthew;Jackman, Shaun;Krzywinski, Martin;Scott, David W.;Trinh, Diane L.;Tamura-Wells, Jessica;Li, Sa;Firme, Marlo R.;Rogic, Sanja;Griffith, Malachi;Chan, Susanna;Yakovenko, Oleksandr;Meyer, Irmtraud M.;Zhao, Eric Y.;Smailus, Duane;Moksa, Michelle;Chittaranjan, Suganthi;Rimsza, Lisa;Brooks-Wilson, Angela;Spinelli, John J.;Ben-Neriah, Susana;Meissner, Barbara;Woolcock, Bruce;Boyle, Merrill;McDonald, Helen;Tam, Angela;Zhao, Yongjun;Delaney, Allen;Zeng, Thomas;Tse, Kane;Butterfield, Yaron;Birol, Inanc;Holt, Rob;Schein, Jacqueline;Horsman, Douglas E.;Moore, Richard;Jones, Steven J. M.;Connors, Joseph M.;Hirst, Martin;Gascoyne, Randy D.;Marra, Marco A.

Mots clés : Lymphome; Biologie (Aberrations chromosomiques)

Menée sur 6 cas de lymphome diffus à grandes cellules B, cette étude analyse l'ensemble du génome codant et évalue la fréquence des mutations

Analysis of the coding genome of diffuse large B-cell lymphoma
• Nature Genetics, sous presse, 2011 (résumé)

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Menée sur 6 cas de lymphome diffus à grandes cellules B, cette étude analyse l'ensemble du génome codant et évalue la fréquence des mutations

“Analysis of the coding genome of diffuse large B-cell lymphoma”

• Pasqualucci, Laura;Trifonov, Vladimir;Fabbri, Giulia;Ma, Jing;Rossi, Davide;Chiarenza, Annalisa;Wells, Victoria A.;Grunn, Adina;Messina, Monica;Elliot, Oliver;Chan, Joseph;Bhagat, Govind;Chadburn, Amy;Gaidano, Gianluca;Mullighan, Charles G.;Rabadan, Raul;Dalla-Favera, Riccardo

Mots clés : Lymphome; Biologie (Aberrations chromosomiques)

Menée sur 74 cas de carcinome épidermoïde de la tête et du cou, cette étude de séquençage des exons identifie un ensemble de gènes mutés qui, notamment, sont impliqués dans la différenciation épidermoïde

The Mutational Landscape of Head and Neck Squamous Cell Carcinoma
• Science, sous presse, 2011 (résumé)

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Menée sur 74 cas de carcinome épidermoïde de la tête et du cou, cette étude de séquençage des exons identifie un ensemble de gènes mutés qui, notamment, sont impliqués dans la différenciation épidermoïde

“The Mutational Landscape of Head and Neck Squamous Cell Carcinoma”

• Stransky, Nicolas;Egloff, Ann Marie;Tward, Aaron D.;Kostic, Aleksandar D.;Cibulskis, Kristian;Sivachenko, Andrey;Kryukov, Gregory V.;Lawrence, Michael;Sougnez, Carrie;McKenna, Aaron;Shefler, Erica;Ramos, Alex H.;Stojanov, Petar;Carter, Scott L.;Voet, Douglas;Cortés, Maria L;Auclair, Daniel;Berger, Michael F.;Saksena, Gordon;Guiducci, Candace;Onofrio, Robert;Parkin, Melissa;Romkes, Marjorie;Weissfeld, Joel L.;Seethala, Raja R.;Wang, Lin;Rangel-Escareño, Claudia;Fernandez-Lopez, Juan Carlos;Hidalgo-Miranda, Alfredo;Melendez-Zajgla, Jorge;Winckler, Wendy;Ardlie, Kristin;Gabriel, Stacey B.;Meyerson, Matthew;Lander, Eric S.;Getz, Gad;Golub, Todd R.;Garraway, Levi A.;Grandis, Jennifer R.

Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papilloma virus was detectable by sequencing of DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), the analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (e.g., NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.

Mots clés : Voies aérodigestives supérieures; Biologie (Aberrations chromosomiques)

Menée sur 19 cas de tumeurs intracanalaires papillaires et mucineuses du pancréas, cette étude identifie des mutations du gène GNAS associées au développement de néoplasies pancréatiques

Recurrent GNAS Mutations Define an Unexpected Pathway for Pancreatic Cyst Development
• Science Translational Medicine, Vol. 3 (92), pp. 92ra66, 2011 (résumé)

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Menée sur 19 cas de tumeurs intracanalaires papillaires et mucineuses du pancréas, cette étude identifie des mutations du gène GNAS associées au développement de néoplasies pancréatiques

“Recurrent GNAS Mutations Define an Unexpected Pathway for Pancreatic Cyst Development”

• Wu, Jian;Matthaei, Hanno;Maitra, Anirban;Dal Molin, Marco;Wood, Laura D.;Eshleman, James R.;Goggins, Michael;Canto, Marcia I.;Schulick, Richard D.;Edil, Barish H.;Wolfgang, Christopher L.;Klein, Alison P.;Diaz, Luis A.;Allen, Peter J.;Schmidt, C. Max;Kinzler, Kenneth W.;Papadopoulos, Nickolas;Hruban, Ralph H.;Vogelstein, Bert

More than 2% of the adult U.S. population harbors a pancreatic cyst. These often pose a difficult management problem because conventional criteria cannot always distinguish cysts with malignant potential from those that are innocuous. One of the most common cystic neoplasms of the pancreas, and a bona fide precursor to invasive adenocarcinoma, is called intraductal papillary mucinous neoplasm (IPMN). To help reveal the pathogenesis of these lesions, we purified the DNA from IPMN cyst fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. In addition to the expected KRAS mutations, we identified recurrent mutations at codon 201 of GNAS. A larger number (113) of additional IPMNs were then analyzed to determine the prevalence of KRAS and GNAS mutations. In total, we found that GNAS mutations were present in 66% of IPMNs and that either KRAS or GNAS mutations could be identified in 96%. In eight cases, we could investigate invasive ...

Mots clés : Pancréas; Biologie (Aberrations chromosomiques)

Oncogènes et suppresseurs de tumeurs

Cet article propose un nouveau modèle qui, sur un mode continu, rend compte de la fonction des gènes suppresseurs de tumeurs et du rôle de leurs mutations dans le cancer

A continuum model for tumour suppression
• Nature, Vol. 476 (7359), pp. 163-169, 2011 (résumé)

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Cet article propose un nouveau modèle qui, sur un mode continu, rend compte de la fonction des gènes suppresseurs de tumeurs et du rôle de leurs mutations dans le cancer

“A continuum model for tumour suppression”

• Berger, Alice H.;Knudson, Alfred G.;Pandolfi, Pier Paolo

Mots clés : Biologie (Oncogènes et suppresseurs de tumeurs)

Menée sur une trentaine de lignées cellulaires de cancer du sein, cette étude identifie des ensembles de gènes associés au développement de différents sous-types de cancer du sein

Functional Viability Profiles of Breast Cancer
• Cancer Discovery, sous presse, 2011 (résumé)

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Menée sur une trentaine de lignées cellulaires de cancer du sein, cette étude identifie des ensembles de gènes associés au développement de différents sous-types de cancer du sein

“Functional Viability Profiles of Breast Cancer”

• Brough, Rachel;Frankum, Jessica R.;Sims, David;Mackay, Alan;Mendes-Pereira, Ana M.;Bajrami, Ilirjana;Costa-Cabral, Sara;Rafiq, Rumana;Ahmad, Amar S.;Cerone, Maria Antonietta;Natrajan, Rachael;Sharpe, Rachel;Shiu, Kai-Keen;Wetterskog, Daniel;Dedes, Konstantine J.;Lambros, Maryou B.;Rawjee, Teeara;Linardopoulos, Spiros;Reis-Filho, Jorge S.;Turner, Nicholas C.;Lord, Christopher J.;Ashworth, Alan

The design of targeted therapeutic strategies for cancer has largely been driven by the identification of tumor-specific genetic changes. However, the large number of genetic alterations present in tumor cells means that it is difficult to discriminate between genes that are critical for maintaining the disease state and those that are merely coincidental. Even when critical genes can be identified, directly targeting these is often challenging, meaning that alternative strategies such as exploiting synthetic lethality may be beneficial. To address these issues, we have carried out a functional genetic screen in >30 commonly used models of breast cancer to identify genes critical to the growth of specific breast cancer subtypes. In particular, we describe potential new therapeutic targets for PTEN-mutated cancers and for estrogen receptor–positive breast cancers. We also show that large-scale functional profiling allows the classification of breast cancers into subgroups distinct ...

Mots clés : Sein; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée sur un modèle murin, cette étude montre que le facteur nucléaire I/B joue un rôle d'oncogène dans le cancer du poumon à petites cellules

Nuclear factor I/B is an oncogene in small cell lung cancer
• Genes & Development, Vol. 25 (14), pp. 1470-1475, 2011 (résumé)

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Menée sur un modèle murin, cette étude montre que le facteur nucléaire I/B joue un rôle d'oncogène dans le cancer du poumon à petites cellules

“Nuclear factor I/B is an oncogene in small cell lung cancer”

• Dooley, Alison L.;Winslow, Monte M.;Chiang, Derek Y.;Banerji, Shantanu;Stransky, Nicolas;Dayton, Talya L.;Snyder, Eric L.;Senna, Stephanie;Whittaker, Charles A.;Bronson, Roderick T.;Crowley, Denise;Barretina, Jordi;Garraway, Levi;Meyerson, Matthew;Jacks, Tyler

Small cell lung cancer (SCLC) is an aggressive cancer often diagnosed after it has metastasized. Despite the need to better understand this disease, SCLC remains poorly characterized at the molecular and genomic levels. Using a genetically engineered mouse model of SCLC driven by conditional deletion of Trp53 and Rb1 in the lung, we identified several frequent, high-magnitude focal DNA copy number alterations in SCLC. We uncovered amplification of a novel, oncogenic transcription factor, Nuclear factor I/B (Nfib), in the mouse SCLC model and in human SCLC. Functional studies indicate that NFIB regulates cell viability and proliferation during transformation.

Mots clés : Poumon; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée in vitro, cette étude identifie un mécanisme de létalité synthétique entre l'hème oxygénase et la fumarate hydratase, qui joue un rôle de suppresseur de tumeurs, dans une maladie génétique rare, la léiomyomatose familiale et cancer du rein

Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase
• Nature, sous presse, 2011 (résumé)

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Menée in vitro, cette étude identifie un mécanisme de létalité synthétique entre l'hème oxygénase et la fumarate hydratase, qui joue un rôle de suppresseur de tumeurs, dans une maladie génétique rare, la léiomyomatose familiale et cancer du rein

“Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase”

• Frezza, Christian;Zheng, Liang;Folger, Ori;Rajagopalan, Kartik N.;MacKenzie, Elaine D.;Jerby, Livnat;Micaroni, Massimo;Chaneton, Barbara;Adam, Julie;Hedley, Ann;Kalna, Gabriela;Tomlinson, Ian P. M.;Pollard, Patrick J.;Watson, Dave G.;Deberardinis, Ralph J.;Shlomi, Tomer;Ruppin, Eytan;Gottlieb, Eyal

Mots clés : Biologie (Oncogènes et suppresseurs de tumeurs)

Menée initialement sur 9 cas de carcinome à cellules transitionnelles, la forme la plus fréquente de cancer de la vessie, puis sur 88 cas complémentaires, cette étude identifie de fréquentes mutations de gènes impliqués dans le remodelage de la chromatine

Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder
• Nature Genetics, sous presse, 2011 (résumé)

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Menée initialement sur 9 cas de carcinome à cellules transitionnelles, la forme la plus fréquente de cancer de la vessie, puis sur 88 cas complémentaires, cette étude identifie de fréquentes mutations de gènes impliqués dans le remodelage de la chromatine

“Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder”

• Gui, Yaoting;Guo, Guangwu;Huang, Yi;Hu, Xueda;Tang, Aifa;Gao, Shengjie;Wu, Renhua;Chen, Chao;Li, Xianxin;Zhou, Liang;He, Minghui;Li, Zesong;Sun, Xiaojuan;Jia, Wenlong;Chen, Jinnong;Yang, Shangming;Zhou, Fangjian;Zhao, Xiaokun;Wan, Shengqing;Ye, Rui;Liang, Chaozhao;Liu, Zhisheng;Huang, Peide;Liu, Chunxiao;Jiang, Hui;Wang, Yong;Zheng, Hancheng;Sun, Liang;Liu, Xingwang;Jiang, Zhimao;Feng, Dafei;Chen, Jing;Wu, Song;Zou, Jing;Zhang, Zhongfu;Yang, Ruilin;Zhao, Jun;Xu, Congjie;Yin, Weihua;Guan, Zhichen;Ye, Jiongxian;Zhang, Hong;Li, Jingxiang;Kristiansen, Karsten;Nickerson, Michael L.;Theodorescu, Dan;Li, Yingrui;Zhang, Xiuqing;Li, Songgang;Wang, Jian;Yang, Huanming;Wang, Jun;Cai, Zhiming

Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer.

Mots clés : Vessie; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée sur 10 cas de carcinome hépatocellulaire associé au virus de l'hépatite C, cette étude identifie des mutations inactivant un gène impliqué dans le remodelage de la chromatine, ARID2

Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma
• Nature Genetics, sous presse, 2011 (résumé)

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Menée sur 10 cas de carcinome hépatocellulaire associé au virus de l'hépatite C, cette étude identifie des mutations inactivant un gène impliqué dans le remodelage de la chromatine, ARID2

“Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma”

• Li, Meng;Zhao, Hong;Zhang, Xiaosong;Wood, Laura D.;Anders, Robert A.;Choti, Michael A.;Pawlik, Timothy M.;Daniel, Hubert D.;Kannangai, Rajesh;Offerhaus, G. Johan A.;Velculescu, Victor E.;Wang, Linfang;Zhou, Shibin;Vogelstein, Bert;Hruban, Ralph H.;Papadopoulos, Nick;Cai, Jianqiang;Torbenson, Michael S.;Kinzler, Kenneth W.

Mots clés : Foie; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée à l'aide d'ARN interférents sur un modèle murin de leucémie myéloïde aiguë, cette étude identifie le rôle essentiel joué par le gène Brd4 dans la maladie

RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia
• Nature, sous presse, 2011 (résumé)

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Menée à l'aide d'ARN interférents sur un modèle murin de leucémie myéloïde aiguë, cette étude identifie le rôle essentiel joué par le gène Brd4 dans la maladie

“RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia”

• Zuber, Johannes;Shi, Junwei;Wang, Eric;Rappaport, Amy R.;Herrmann, Harald;Sison, Edward A.;Magoon, Daniel;Qi, Jun;Blatt, Katharina;Wunderlich, Mark;Taylor, Meredith J.;Johns, Christopher;Chicas, Agustin;Mulloy, James C.;Kogan, Scott C.;Brown, Patrick;Valent, Peter;Bradner, James E.;Lowe, Scott W.;Vakoc, Christopher R.

Mots clés : Leucémie; Biologie (Oncogènes et suppresseurs de tumeurs)

Progression et métastases

Menée in vitro et à l'aide de xénogreffes, cette étude montre le rôle joué par le facteur de croissance du tissu conjonctif dans le processus invasif des gliomes

Effect of Brain- and Tumor-Derived Connective Tissue Growth Factor on Glioma Invasion
• Journal of the National Cancer Institute, sous presse, 2011 (résumé)

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Menée in vitro et à l'aide de xénogreffes, cette étude montre le rôle joué par le facteur de croissance du tissu conjonctif dans le processus invasif des gliomes

“Effect of Brain- and Tumor-Derived Connective Tissue Growth Factor on Glioma Invasion”

• Edwards, Lincoln A.;Woolard, Kevin;Son, Myung Jin;Li, Aiguo;Lee, Jeongwu;Ene, Chibawanye;Mantey, Samuel A.;Maric, Dragan;Song, Hua;Belova, Galina;Jensen, Robert T.;Zhang, Wei;Fine, Howard A.

Background Tumor cell invasion is the principal cause of treatment failure and death among patients with malignant gliomas. Connective tissue growth factor (CTGF) has been previously implicated in cancer metastasis and invasion in various tumors. We explored the mechanism of CTGF-mediated glioma cell infiltration and examined potential therapeutic targets.Methods Highly infiltrative patient-derived glioma tumor–initiating or tumor stem cells (TIC/TSCs) were harvested and used to explore a CTGF-induced signal transduction pathway via luciferase reporter assays, chromatin immunoprecipitation (ChIP), real-time polymerase chain reaction, and immunoblotting. Treatment of TIC/TSCs with small-molecule inhibitors targeting integrin β1 (ITGB1) and the tyrosine kinase receptor type A (TrkA), and short hairpin RNAs targeting CTGF directly were used to reduce the levels of key protein components of CTGF-induced cancer infiltration. TIC/TSC infiltration was examined in real-time cell migration ...
Connective Tissue Growth Factor and the Parallels Between Brain Injury and Brain Tumors
• Journal of the National Cancer Institute, sous presse, 2011 (éditorial)

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Menée in vitro et à l'aide de xénogreffes, cette étude montre le rôle joué par le facteur de croissance du tissu conjonctif dans le processus invasif des gliomes

“Connective Tissue Growth Factor and the Parallels Between Brain Injury and Brain Tumors”

• Halliday, John J. ; Holland, Eric C.

Mots clés : Système nerveux central; Biologie (Progression et métastases)

Menée sur des lignées cellulaires de cancer du sein, cette étude analyse la dynamique des populations cellulaires et, notamment, élabore un modèle prédictif de l'émergence des cellules souches cancéreuses

Stochastic State Transitions Give Rise to Phenotypic Equilibrium in Populations of Cancer Cells
• Cell, Vol. 146 (4), pp. 633-644, 2011 (résumé)

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Menée sur des lignées cellulaires de cancer du sein, cette étude analyse la dynamique des populations cellulaires et, notamment, élabore un modèle prédictif de l'émergence des cellules souches cancéreuses

“Stochastic State Transitions Give Rise to Phenotypic Equilibrium in Populations of Cancer Cells”

• Gupta, Piyush B;Fillmore, Christine M;Jiang, Guozhi;Shapira, Sagi D;Tao, Kai;Kuperwasser, Charlotte;Lander, Eric S

Cancer cells within individual tumors often exist in distinct phenotypic states that differ in functional attributes. While cancer cell populations typically display distinctive equilibria in the proportion of cells in various states, the mechanisms by which this occurs are poorly understood. Here, we study the dynamics of phenotypic proportions in human breast cancer cell lines. We show that subpopulations of cells purified for a given phenotypic state return towards equilibrium proportions over time. These observations can be explained by a Markov model in which cells transition stochastically between states. A prediction of this model is that, given certain conditions, any subpopulation of cells will return to equilibrium phenotypic proportions over time. A second prediction is that breast cancer stem-like cells arise de novo from non-stem-like cells. These findings contribute to our understanding of cancer heterogeneity and reveal how stochasticity in single-cell behaviors ...

Mots clés : Sein; Biologie (Progression et métastases)

Menées sur diverses lignées cellulaires et sur des souches de levure, ces deux études analysent le rôle de l'aneuploïdie dans les cancers

Aneuploidy Drives a Mutator Phenotype in Cancer
• Science, Vol. 333 (6045), pp. 942-943, 2011 (résumé)

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Menées sur diverses lignées cellulaires et sur des souches de levure, ces deux études analysent le rôle de l'aneuploïdie dans les cancers

“Aneuploidy Drives a Mutator Phenotype in Cancer”

• Kolodner, Richard D.;Cleveland, Don W.;Putnam, Christopher D.
Aneuploidy Drives Genomic Instability in Yeast
• Science, Vol. 333 (6045), pp. 1026-1030, 2011 (résumé)

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Menées sur diverses lignées cellulaires et sur des souches de levure, ces deux études analysent le rôle de l'aneuploïdie dans les cancers

“Aneuploidy Drives Genomic Instability in Yeast”

• Sheltzer, Jason M. ; Blank, Heidi M. ; Pfau, Sarah J. ; Tange, Yoshie ; George, Benson M. ; Humpton, Timothy J. ; Brito, Ilana L. ; Hiraoka, Yasushi ; Niwa, Osami ; Amon, Angelika

Aneuploidy decreases cellular fitness, yet it is also associated with cancer, a disease of enhanced proliferative capacity. To investigate one mechanism by which aneuploidy could contribute to tumorigenesis, we examined the effects of aneuploidy on genomic stability. We analyzed 13 budding yeast strains that carry extra copies of single chromosomes and found that all aneuploid strains exhibited one or more forms of genomic instability. Most strains displayed increased chromosome loss and mitotic recombination, as well as defective DNA damage repair. Aneuploid fission yeast strains also exhibited defects in mitotic recombination. Aneuploidy-induced genomic instability could facilitate the development of genetic alterations that drive malignant growth in cancer.
Mutational Inactivation of STAG2 Causes Aneuploidy in Human Cancer
• Science, Vol. 333 (6045), pp. 1039-1043, 2011 (résumé)

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Menées sur diverses lignées cellulaires et sur des souches de levure, ces deux études analysent le rôle de l'aneuploïdie dans les cancers

“Mutational Inactivation of STAG2 Causes Aneuploidy in Human Cancer”

• Solomon, David A. ; Kim, Taeyeon ; Diaz-Martinez, Laura A. ; Fair, Joshlean ; Elkahloun, Abdel G. ; Harris, Brent T. ; Toretsky, Jeffrey A. ; Rosenberg, Steven A. ; Shukla, Neerav ; Ladanyi, Marc ; Samuels, Yardena ; James, C. David ; Yu, Hongtao ; Kim, Jung-Sik ; Waldman, Todd

Most cancer cells are characterized by aneuploidy, an abnormal number of chromosomes. We have identified a clue to the mechanistic origins of aneuploidy through integrative genomic analyses of human tumors. A diverse range of tumor types were found to harbor deletions or inactivating mutations of STAG2, a gene encoding a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Because STAG2 is on the X chromosome, its inactivation requires only a single mutational event. Studying a near-diploid human cell line with a stable karyotype, we found that targeted inactivation of STAG2 led to chromatid cohesion defects and aneuploidy, whereas in two aneuploid human glioblastoma cell lines, targeted correction of the endogenous mutant alleles of STAG2 led to enhanced chromosomal stability. Thus, genetic disruption of cohesin is a cause of aneuploidy in human cancer.

Mots clés : Biologie (Progression et métastases)

Menée à l'aide de modèles murins, cette étude identifie un mécanisme par lequel les micro-ARNs 200 favorisent une colonisation métastatique

Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization
• Nature Medicine, sous presse, 2011 (résumé)

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Menée à l'aide de modèles murins, cette étude identifie un mécanisme par lequel les micro-ARNs 200 favorisent une colonisation métastatique

“Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization”

• Korpal, Manav;Ell, Brian J.;Buffa, Francesca M.;Ibrahim, Toni;Blanco, Mario A.;Celia-Terrassa, Toni;Mercatali, Laura;Khan, Zia;Goodarzi, Hani;Hua, Yuling;Wei, Yong;Hu, Guohong;Garcia, Benjamin A.;Ragoussis, Jiannis;Amadori, Dino;Harris, Adrian L.;Kang, Yibin

Although the role of miR-200s in regulating E-cadherin expression and epithelial-to-mesenchymal transition is well established, their influence on metastatic colonization remains controversial. Here we have used clinical and experimental models of breast cancer metastasis to discover a pro-metastatic role of miR-200s that goes beyond their regulation of E-cadherin and epithelial phenotype. Overexpression of miR-200s is associated with increased risk of metastasis in breast cancer and promotes metastatic colonization in mouse models, phenotypes that cannot be recapitulated by E-cadherin expression alone. Genomic and proteomic analyses revealed global shifts in gene expression upon miR-200 overexpression toward that of highly metastatic cells. miR-200s promote metastatic colonization partly through direct targeting of Sec23a, which mediates secretion of metastasis-suppressive proteins, including Igfbp4 and Tinagl1, as validated by functional and clinical correlation studies. Overall, ...

Mots clés : Sein; Biologie (Progression et métastases)

Cet article passe en revue le rôle du second messager cellulaire Ca2+ dans le processus métastatique

Calcium in tumour metastasis: new roles for known actors
• Nature Reviews Cancer, Vol. 11 (8), pp. 609-618, 2011 (résumé)

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Cet article passe en revue le rôle du second messager cellulaire Ca2+ dans le processus métastatique

“Calcium in tumour metastasis: new roles for known actors”

• Prevarskaya, Natalia;Skryma, Roman;Shuba, Yaroslav

In most cases, metastasis, not the primary tumour per se, is the main cause of mortality in cancer patients. In order to effectively escape the tumour, enter the circulation and establish secondary growth in distant organs cancer cells must develop an enhanced propensity to migrate. The ubiquitous second messenger Ca2+ is a crucial regulator of cell migration. Recently, a number of known molecular players in cellular Ca2+ homeostasis, including calcium release-activated calcium channel protein 1 (ORAI1), stromal interaction molecule 1 (STIM1) and transient receptor potential (TRP) channels, have been implicated in tumour cell migration and the metastatic cell phenotype. We discuss how these developments have increased our understanding of the Ca2+ dependence of pro-metastatic behaviours.

Mots clés : Biologie (Progression et métastases)

Cet article passe en revue le rôle de la chiomiotaxie des cellules tumorales et stromales dans la progression des cancers

Chemotaxis in cancer
• Nature Reviews Cancer, Vol. 11 (8), pp. 573-587, 2011 (résumé)

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Cet article passe en revue le rôle de la chiomiotaxie des cellules tumorales et stromales dans la progression des cancers

“Chemotaxis in cancer”

• Roussos, Evanthia T.;Condeelis, John S.;Patsialou, Antonia

Chemotaxis of tumour cells and stromal cells in the surrounding microenvironment is an essential component of tumour dissemination during progression and metastasis. This Review summarizes how chemotaxis directs the different behaviours of tumour cells and stromal cells in vivo, how molecular pathways regulate chemotaxis in tumour cells and how chemotaxis choreographs cell behaviour to shape the tumour microenvironment and to determine metastatic spread. The central importance of chemotaxis in cancer progression is highlighted by discussion of the use of chemotaxis as a prognostic marker, a treatment end point and a target of therapeutic intervention.

Mots clés : Biologie (Progression et métastases)

Menée sur des lignées cellulaires de cancer du sein et à l'aide d'un modèle murin, cette étude identifie le rôle de la protéine d'adhésion focale Kindlin-1 dans la formation de métastases pulmonaires

Role of the Focal Adhesion Protein Kindlin-1 in Breast Cancer Growth and Lung Metastasis
• Journal of the National Cancer Institute, sous presse, 2011 (résumé)

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Menée sur des lignées cellulaires de cancer du sein et à l'aide d'un modèle murin, cette étude identifie le rôle de la protéine d'adhésion focale Kindlin-1 dans la formation de métastases pulmonaires

“Role of the Focal Adhesion Protein Kindlin-1 in Breast Cancer Growth and Lung Metastasis”

• Sin, Soraya;Bonin, Florian;Petit, Valérie;Meseure, Didier;Lallemand, François;Bièche, Ivan;Bellahcène, Akeila;Castronovo, Vincent;de Wever, Olivier;Gespach, Christian;Lidereau, Rosette;Driouch, Keltouma

Background Fermitin family member 1 (FERMT1, Kindlin-1) is an epithelial-specific regulator of integrin functions and is associated with Kindler syndrome, a genetic disorder characterized by skin blistering, atrophy, and photosensitivity. However, the possible role of kindlin-1 in cancer remains unknown.Methods Kindlin-1 expression was quantified in several human cancers using quantitative real-time polymerase chain reaction and published microarray datasets. The association between kindlin-1 expression and patient metastasis-free survival (N = 516) was assessed with Kaplan–Meier analyses. Effects of ectopic expression or silencing of kindlin-1 on cell signaling, migration, and invasion were assessed in human breast cancer cell lines using western blotting, immunofluorescence, wound healing assays, and invasion on Matrigel or type I collagen substrates. Breast tumor growth and lung metastasis were evaluated in 12-week-old female BALB/c mice (10 controls and six Kindlin-1-knockdown ...

Mots clés : Sein; Biologie (Progression et métastases)

Ressources et infrastructures (Biologie)

Cette étude décrit une nouvelle méthode, basée sur des semi-conducteurs, pour séquencer l'ADN sans recourir à des moyens optiques

An integrated semiconductor device enabling non-optical genome sequencing
• Nature, Vol. 475 (7356), pp. 348-352, 2011 (article en libre accès)

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Cette étude décrit une nouvelle méthode, basée sur des semi-conducteurs, pour séquencer l'ADN sans recourir à des moyens optiques

“An integrated semiconductor device enabling non-optical genome sequencing”

• Rothberg, Jonathan M.;Hinz, Wolfgang;Rearick, Todd M.;Schultz, Jonathan;Mileski, William;Davey, Mel;Leamon, John H.;Johnson, Kim;Milgrew, Mark J.;Edwards, Matthew;Hoon, Jeremy;Simons, Jan F.;Marran, David;Myers, Jason W.;Davidson, John F.;Branting, Annika;Nobile, John R.;Puc, Bernard P.;Light, David;Clark, Travis A.;Huber, Martin;Branciforte, Jeffrey T.;Stoner, Isaac B.;Cawley, Simon E.;Lyons, Michael;Fu, Yutao;Homer, Nils;Sedova, Marina;Miao, Xin;Reed, Brian;Sabina, Jeffrey;Feierstein, Erika;Schorn, Michelle;Alanjary, Mohammad;Dimalanta, Eileen;Dressman, Devin;Kasinskas, Rachel;Sokolsky, Tanya;Fidanza, Jacqueline A.;Namsaraev, Eugeni;McKernan, Kevin J.;Williams, Alan;Roth, G. Thomas;Bustillo, James

The seminal importance of DNA sequencing to the life sciences, biotechnology and medicine has driven the search for more scalable and lower-cost solutions. Here we describe a DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes. Sequence data are obtained by directly sensing the ions produced by template-directed DNA polymerase synthesis using all-natural nucleotides on this massively parallel semiconductor-sensing device or ion chip. The ion chip contains ion-sensitive, field-effect transistor-based sensors in perfect register with 1.2 million wells, which provide confinement and allow parallel, simultaneous detection of independent sequencing reactions. Use of the most widely used technology for constructing integrated circuits, the complementary metal-oxide semiconductor (CMOS) process, allows for low-cost, large-scale production and scaling ...